rare actino

26
See discussions, stats, and author profiles for this publication at: http://www.researchgate.net/publication/51171766 Rare actinomycetes: A potential storehouse for novel antibiotics ARTICLE in CRITICAL REVIEWS IN BIOTECHNOLOGY · MAY 2011 Impact Factor: 7.84 · DOI: 10.3109/07388551.2011.562482 · Source: PubMed CITATIONS 31 DOWNLOADS 1,662 VIEWS 567 Available from: Kavita Tiwari Retrieved on: 05 September 2015

Upload: mac1er

Post on 01-Feb-2016

243 views

Category:

Documents


0 download

DESCRIPTION

actinomycetes rares

TRANSCRIPT

Page 2: Rare Actino

108

The rationale for rare actinomycetes

There is a continued need to bio-prospect alternative sources of natural products (Donadio et al., 2002). Demain (2002) suggested that to build a library of unique chemi-cal diversity, microbial, and plant secondary metabolites offer the best possibility. Although available in abun-dance, so far, it is estimated that less than 1% of all the existing microorganisms have been identified and char-acterized (Amann et al., 1995). There is still a large pool of uncultured microorganisms in natural environments.

Soil and water are rich resources, and offer a bounti-ful supply of potentially novel microorganisms, which can be exploited in natural product screening programs (Long et al., 1994). Apparently 99% of the diverse bacte-rial species are unexplored (Davies, 1999; Ward et al., 1990; Watve et al., 2000). Stephen Zinder (2002), in his “crystal ball”, foresaw many significant free-living uncul-tured microorganisms, found in our environment, being cultured.

Microorganisms evolve their secondary metabolic pathways, to produce compounds displaying an impres-sive and diverse array of biological activity (Perić-Concha and Long, 2003). They have proven ability to produce secondary metabolites and to introduce functionality, such as chirality by biotransformation. However, not all microorganisms can produce secondary metabolites with equanimity.

Within the prokaryotic world, the filamentous actino-mycetes, the myxobacteria, the pseudomonads, and the cyanobacteria; and among the eukaryotic microbes, the filamentous fungi have the potential to produce many chemically diverse metabolites (Donadio et al., 2002). In their paper Donadio et al. (2002) stated, “more novel metabolites can still be discovered by screening unusual or difficult to isolate strains belonging to the two most prolific groups of producers, the filamentous actinomy-cetes and the fungi”. These authors further suggest certain critical factors that must be considered while embarking

REVIEW ARTICLE

Rare actinomycetes: a potential storehouse for novel antibiotics

Kavita Tiwari and Rajinder K. Gupta

School of Biotechnology, Guru Gobind Singh Indraprastha University, Delhi, India

AbstractNew antimicrobial agents are desperately needed to combat the increasing number of antibiotic resistant strains of pathogenic microorganisms. Natural products remain the most propitious source of novel antibiotics. It is widely accepted that actinobacteria are prolific producers of natural bioactive compounds. We argue that the likelihood of discovering a new compound having a novel chemical structure can be increased with intensive efforts in isolating and screening rare genera of microorganisms. Screening rare actinomycetes and their previously under-represented genera from unexplored environments in natural product screening collections is one way of achieving this. Rare actinomycetes are usually regarded as the actinomycete strains whose isolation frequency is much lower than that of the streptomycete strains isolated by conventional methods. Many natural environments are still either unexplored or under-explored and thus, can be considered as a prolific resource for the isolation of less exploited microorganisms. More and different ecological niches need to be studied as sources of a greater diversity of novel microorganisms. In this review, we wish to update our understanding of the potential of the rare actinomycetes by focusing on the ways and means of enhancing their bio-discovery potential.Keywords: Rare actinomycetes, antibiotics, Actinomadura, Actinoplanes, Dactylosporangium, Kibdelosporangium, Microbispora, Micromonospora, Salinospora, Streptosporangium, Verrucosispora

Address for Correspondence: Rajinder K. Gupta, School of Biotechnology, Guru Gobind Singh Indraprastha University, Dwarka, New Delhi 110075, India. Tel: +91-11-25302301. Fax: +91-11-25302302. E-mail: [email protected]

(Received 09 April 2010; revised 05 February 2011; accepted 09 February 2011)

Critical Reviews in Biotechnology, 2012; 32(2): 108–132© 2012 Informa Healthcare USA, Inc.ISSN 0738-8551 print/ISSN 1549-7801 onlineDOI: 10.3109/07388551.2011.562482

Critical Reviews in Biotechnology

2012

32

2

108

132

09 April 2010

05 February 2011

09 February 2011

0738-8551

1549-7801

© 2012 Informa Healthcare USA, Inc.

10.3109/07388551.2011.562482

BBTN

562482

Cri

tical

Rev

iew

s in

Bio

tech

nolo

gy D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y In

dian

Ins

titut

e of

Tec

hnol

ogy

New

Del

hi o

n 05

/18/

12Fo

r pe

rson

al u

se o

nly.

Page 3: Rare Actino

Rare actinomycetes: a potential storehouse for novel antibiotics 109

© 2012 Informa Healthcare USA, Inc.

on a screening program for finding novel bioactive com-pounds from microbes. These are, first, the number of strains to be screened along with their degree of diversity, and secondly, their unique potential to produce novel metabolites.

These two criteria are indeed crucial because inten-sively screened microorganisms are more likely to yield known metabolites, than the ones that have been less extensively exploited. The notion that microbial diversity allows continuous identification of neo-bioactive com-pounds is indisputable. Moreover, such molecules have original and unforeseen structures, and are selective inhibitors of their molecular targets

Actinomycetes constitute a significant portion of soil micro flora and are widely distributed in soil (Goodfellow, 1983). If one considers the estimate that a gram of fresh soil contains about 109 colony-forming units of bacteria, of which 107 is actinomycete (Steffan et al., 1988; Weinbauer et al., 1998). It can be concluded that bio-diversity can provide us with an overwhelming reservoir of potentially active compounds. Efforts should be encouraged to har-ness the chemical diversity from actinomycetes. A genus previously un-exploited from unexplored habitats in the natural product screening collection warrants particular attention, as suggested by Donadio et al. (2002). Recent reports on the isolation and characterization of novel actinomycetes from poorly researched habitats illus-trate the potential of this approach (Bredholt et al., 2008; Eccleston et al., 2008; Okoro et al., 2009). Therefore, we opine that by screening such organisms, the prospects of discovering new natural products increase, which can later be developed as a resource for biotechnology.

The oceans are home to a huge microbial diversity and population (Sogin et al., 2006; Stach and Bull, 2005). They are also being screened intensively throughout the world for their biodiversity potential. Moreover, until now, representatives of a relatively few taxa have been isolated from marine as opposed to terrestrial habitats (Goodfellow, 2010). Thus, considering the vastness of marine environment, the potential rewards of this trea-sure house represented by the oceans are unimaginable.

A combination of selective isolation and screening procedures to a relatively small number of de-replicated novel actinomycetes isolated from geographically diverse marine sediment samples can lead to the discovery of neo-compounds (Goodfellow and Fiedler, 2010). Interestingly the latest data reveals a sharp rise in reports pertaining to the marine actinomycetes as a valuable source of novel bioactive compounds (Bull and Stach, 2007; Fiedler et al., 2005). Given this argument, supporting this likeli-hood is the discovery of neo-bioactive compounds from them (Blunt et al., 2007; Fenical and Jensen, 2006; Fiedler et al., 2005; Lam, 2006); several of which are currently in clinical trials (Fenical, 2006). Some antibacterial agents from marine microorganisms, such as salinosporamide A, have even advanced to phase I trials in less than 3 years after their discovery (Fenical and Jensen, 2006). In view of the remarkable diversity of microorganisms from

marine environments and their metabolic products, new techniques are needed to assess their genetic and chemi-cal potential.

We argue that to obtain a novel metabolite, a diverse and less exploited reserve of microbes is required. Isolation of rare actinomycetes, thus, becomes the first and the most crucial step towards actinomycetes resource develop-ment for drug discovery (Cai et al., 2009). Rare actinomy-cetes are usually regarded as the strains of actinomycetes whose isolation frequency is much lower than that of the streptomycete strains isolated by conventional methods. The non-streptomycete actinomycetes are called rare actinomycetes, comprising approximately 220 genera up to September 2010.

Published results so far, show a substantial presence of these genera and a large diversity of unisolated actinomy-cetes in different types of soil. It is assumed that rare actin-omycetes undoubtedly represent an important source of novel secondary metabolites. These assumptions rest on the theory that they have not been intensively screened in the past and are also potentially capable of producing previously unknown secondary metabolites (Sosio et al., 2000). Therefore, we think that the search for novel com-pounds can now be concentrated on the isolation of rare actinomycetes along with the, as before, the main fami-lies of Streptomycetaceae and Micromonosporaceae.

Rare actinomycetes are widely distributed in terres-trial and aquatic ecosystems. Environmental factors such as soil type, pH, humus content, and the characteristics of the humic acid content of the soil affect their distri-bution (Hayakawa, 2008). While rare actinomycetes may result in increased chances of discovering novel struc-tures, their genetics and physiology are poorly known. To speed up their isolation process, the knowledge about distribution of such unexploited groups of micro-organisms must be augmented. Some genera of this group are Actinomadura, Actinoplanes, Amycolatopsis, Actinokineospora, Acrocarpospora, Actinosynnema, Catenuloplanes, Cryptosporangium, Dactylosporangium, Kibdelosporangium, Kineosporia, Kutzneria, Microbiospora, Microtetraspora, Nocardia, Nonomuraea, Planomonospora, Planobispora, Pseudonocardia, Saccharomonospora, Saccharopolyspora, Saccharothrix, Streptosporangium, Spirilliplanes, Thermomonospora, Thermobifida, and Virgosporangium (Lazzarini et al., 2001).

Distribution of antibiotic producing strains

More than 10 000 secondary metabolites of microbial ori-gin have already been discovered (Hamaki et al., 2005). The current arsenal of antimicrobials is mostly derived from natural products that are either of actinomycetes or of fungi (Butler and Buss, 2006; Newman and Cragg, 2007). Of all the practically used antibiotics more than 90% originate from actinomycetes, and about two-thirds of all the discovered bioactive substances of micro-bial origin are produced by them (Hamaki et al., 2005).

Cri

tical

Rev

iew

s in

Bio

tech

nolo

gy D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y In

dian

Ins

titut

e of

Tec

hnol

ogy

New

Del

hi o

n 05

/18/

12Fo

r pe

rson

al u

se o

nly.

Page 4: Rare Actino

110 K. Tiwari and R. K. Gupta

Critical Reviews in Biotechnology

Actinomycetes, thus, become crucial microorganisms in this context.

The antibiotics produced by actinomycetes (and other microbes) have been continuously evolving for over one billion years (Baltz, 2005; Baltz, 2006). It was first discov-ered in the 1940s that about 1% of total actinomycetes isolated from any soil sample produce streptomycin whereas daptomycin producers were discovered only after screening nearly 107 actinomycetes (Baltz, 2008). Furthermore, at least 2000 antibiotics other than strepto-mycin are produced at frequencies spanning this 105 fold range (Baltz, 2008).

In the past, many antibiotics have been obtained and studied, particularly from the members of the genus Streptomyces (Okami and Hotta, 1988). It is estimated that during the 1950s and 1960s, the majority (~70%) of

the antibiotics were discovered from the Streptomyces species alone (Tishkov, 2001). These numbers help us in framing the challenges for future drug discovery endeavors. The ABL database describes more than 8000 antimicrobial products out of which around 45.6% are produced by Streptomyces alone (Lazzarini et al., 2001). As many of the fungal products are either plant toxins or mammalian enzyme inhibitors, fungi produce only 21.5%. Other bacteria produce about 16.9% of anti-in-fectives whereas another 16% is produced by the mem-bers of rare genera of actinomycetes (Lazzarini et al., 2001).

Bentley and coworkers (2002), while looking for genes typical for secondary metabolism, made a striking dis-covery by counting 23 gene clusters from the complete sequence of the S. coelicolor genome. It is safe to assume

Other bacteria16.90%

Rare actinomycetes16.00%

Streptomycetes45.60%

Fungi21.50%

Figure 1. Distribution of different groups of microorganisms producing antibiotics (Biosearch Italia Strain Collection) (Lazzarini, 2001).

Nocardia11.00%

Nocardioides2.60%

Genera incertae sedis13.30%

Streptosporangiaceae6.00% Thermomonosporacea

14.00%

Micromonosporacea38.10%

Pseudonocardiaceae15.00%

Figure 2. Relative distribution of producing strains among rare Actinomycetes (as described in ABL Database according to the recent classification published in the Atlas of Actinomycetes Japan) (Lazzarini, 2001; Website (http://www.nih.go.jp/saj/DigitalAtlas/)).

Cri

tical

Rev

iew

s in

Bio

tech

nolo

gy D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y In

dian

Ins

titut

e of

Tec

hnol

ogy

New

Del

hi o

n 05

/18/

12Fo

r pe

rson

al u

se o

nly.

Page 5: Rare Actino

Rare actinomycetes: a potential storehouse for novel antibiotics 111

© 2012 Informa Healthcare USA, Inc.

Table 1. Diversity of antibiotic compounds discovered as products of Micromonosporaceae (Dactylosporangium, Salinispora and Verrucosispora spp.) and Actinoplanes spp. (Website (http://www.namazu.org/)).Organism Antibiotic Class of compound ReferenceM. fuscus Microcin A & B Peptide Taira & Fugii 1952 (J Antibiot, 5(187)M. carboncea Everninomicin Oligosaccharide Weinstein et al. 1965 (Antimicrob Agents Chemother, pp-24-32)M. megalomicea Megalomicin Macrolide Weinstein et al. 1969 (J Antibiot, 22: 253–258)M. inyoensis 6640 (Sisomicin) Aminoglycoside Weinstein et al. 1970 (J Antibiot, 23: 551-554)M. rosaria Rosamicin Macrolide Wagman et al. 1972 (J Antibiot, 25(11), 641-643)M. inyoensis Mutamicins Aminoglycoside Testa RT et al. 1974 (J Antibiot, 27: 917-921)M. rhodorangea G-418 Aminoglycoside Wagman et al. 1974 (Antimicrob Agents Chemother, 6(2): 144-149)M. sagamiensis var. nonreducans nov. sp.

XK-62-2 (Sagamicin) Aminoglycoside Okachi et al. 1974

(J Antibiot, 27(10), 793-800)M. inositola XK-41 complex (A1, A2, B1,

B2, C)Macrolide Kawamoto et al. 1974

(J Antibiot, 27: 493-501)Micromonospora strain XK-62-2 Aminoglycoside Nara T et al. 1975 (J Antibiot, 28(1), 21-28)M. grisea Verdamicin Aminoglycoside Weinstein et al. 1975 (Antimicrob Agents Chemother, 7(3): 246-249)M. inyoensis Sisomicin components Aminoglycoside Lee BK et al. 1976 (J Antibiot, 29(7), 677-684)M. chalcea Juvenimicins Macrolide Hatano K 1976 (J Antibiot, 29(11): 1163-70)M. zionensis G-52 Aminoglycoside Marquez JA et al. 1976 (J Antibiot, 483-487)M. floridensis Actinomycin complex Polypeptide Wagman et al. 1976 (Antimicrob Agents Chemother 9(3): 465-469)M. purpurea Gentamicin, 2-hydroxy Aminoglycoside Daum SJ 1977 (J Antibiot, 30(1): 98-105)M. capillata sp. M-4365 (A1, A2, A3) & (G1, G2,

G3)Macrolide Furumai T et al. 1977

(J Antibiot, 30(6): 443-9)Micromonospora sp. Fortimicin (A&B) Aminoglycoside Nara T et al. 1977 (J Antibiot, 30(7): 533-40)M. purpurea Gentamicin, deoxy Gentamicin,

hydroxyAminoglycoside Rosi D 1977

(J Antibiot, 30(1): 88-97)M. inyoensis 66-40G Aminoglycoside Kugelman M et al. 1978 (J Antibiot, 31(7): 643-5)M. olivoasterospora Fortimicin E, 4-N-aminoacyl Aminoglycoside Kurath P et al.1979 (J Antibiot, 32(9): 884-90)M. olivoasterospora Fortimicin C, D & KE Aminoglycoside Sugimoto M et al. 1979 (J Antibiot, 32(9): 868-73)Micromonospora sp. Doxorubicin, 11-deoxy Anthracycline glycoside Cassinelli G et al. 1980 (J Antibiot, 33(12): 1468-73) Daunorubicin, 11-deoxy Daunorubicin, 11-deoxy-13-dihydro, Daunorubicin, 11-deoxy-13-deoxoM. chalcea Antlermicin A Aminoglycoside Kobinata K et al. 1980 (J Antibiot, 33(2): 244-6)M. chalcea Antlermicins B & C Aminoglycoside Kobinata K et al. 1980

(Continued)

Cri

tical

Rev

iew

s in

Bio

tech

nolo

gy D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y In

dian

Ins

titut

e of

Tec

hnol

ogy

New

Del

hi o

n 05

/18/

12Fo

r pe

rson

al u

se o

nly.

Page 6: Rare Actino

112 K. Tiwari and R. K. Gupta

Critical Reviews in Biotechnology

Organism Antibiotic Class of compound Reference (J Antibiot, 33(7): 772-5)M. chalcea Tetrocarcin A, B & C Aminoglycoside Tamaoki T et al. 1980 (J Antibiot, 33(9): 946-50)M. griseorubida sp. Mycinamicin I, II, III, IV, V Macrolide Satoi S et al. 1980 (J Antibiot, 33(4): 364-76)M. olivoasterospora Fortimicin A, N-formyl Aminoglycoside Inouye S et al. 1980 (J Antibiot, 33(5): 510-3)M. chalcea Izumenolide Lactones Liu WC et al. 1980 (J Antibiot, 33(11): 1256-61)M. echinospora X-14847 Aminoglycoside Maehr H et al. 1980 (J Antibiot, 33(12): 1431-6)M. chalcea Alanine, N-(2, 6-diamino-6-

hydroxy-methylpimelyl)-L-Oligopeptide Shoji J et al. 1981

(J Antibiot, 34(4): 370-3)M. echinospora Dotriacolide Lactones Ikeda Y et al. 1981 (J Antibiot, 34(12): 1628-30)Micromonospora sp. Combimicin (A1 & A2) (B1 &

B2)Aminoglycoside Oka Y et al. 1981

(J Antibiot, 34(6): 777-81)M. miyakonensis sp. Glycine, L-2-(1-methylcyclo-

propyl)Amino acid Kawamura Y 1981

(J Antibiot, 34(4): 367-73)M. sagamiensis Gentamicin X2, G-418 Aminoglycoside Kase H 1982 (J Antibiot, 35(1): 1-9)M. sagamiensis Sagamicin, 2-hydroxy Aminoglycoside Kitamura S et al. 1982 (J Antibiot, 35(1): 94-7)M. verruculosa M-92, M-92 BN-3 Naphthoquinones Tani K & Takaishi T 1982 (J Antibiot, 35(11): 1437-40) M-92 VA-2, M-92 BA-4 M-92 BA-5, M-92 BN-1 M-92 BN-2 M. chalcea Tetrocarcin E1, E2, F & F-1 Glycosides Tamaoki T et al. 1982 (J Antibiot, 35(8): 979-84)M. sagamiensis SU-1, SU-2 & SU-3 Unknown structure Kase H 1982 (J Antibiot, 35(4): 385-90)M. rosaria Rosaramicin, 20-deoxo-

aglyconeProtylonolide Vaughan RW et al. 1982

(J Antibiot, 35(2): 251-3) Rosaramicin, 20-deoxo-12, 13- desepoxy-12, 13-dehydro-aglyconeM. griseorubida Mycinamicin VI & VII Macrolide Hayashi M et al. 1983 (J Antibiot, 36(2): 175-8)M. polytrota Rosaramicin, 22-hydroxy- Protylonolide Lee BK et al. 1983 23-O- mycinosyl-20-deoxo-20- dihydro-12,13-deepoxy- (J Antibiot, 36(6): 742-4)M. echinospora Hazimicins (5 & 6) Nitriles Marquez et al. 1983 (J Antibiot, 36(9): 1101-8)Micromonospora sp. Dapiramicin Ribonucleosides Shomura T et al. 1983 (J Antibiot, 36(10): 1300-4)M. narashinoensis Rustmicin Macrolides Takatsu T et al. 1985 (J Antibiot, 38(12): 1806-9)M. chalcea Neorustmicin A Macrolides Abe Y et al. 1985 (J Antibiot, 38(12): 1810-2)M. echinospora Clostomicins Macrolide Omura et al. 1986 (J Antibiot, 39(10): 1407-12)M. chalcea Neorustmicin B, C & D Lactones Nakayama H et al. 1986 (J Antibiot, 39(7): 1016-20)M. halophytica K-13 Cyclic Peptides Kase H 1987 (J Antibiot, 40(4): 450-4)

(Continued)

Table 1. (Continued).

Cri

tical

Rev

iew

s in

Bio

tech

nolo

gy D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y In

dian

Ins

titut

e of

Tec

hnol

ogy

New

Del

hi o

n 05

/18/

12Fo

r pe

rson

al u

se o

nly.

Page 7: Rare Actino

Rare actinomycetes: a potential storehouse for novel antibiotics 113

© 2012 Informa Healthcare USA, Inc.

Organism Antibiotic Class of compound Reference

M. olivoasterospora K-259-2 Anthraquinone Matsuda Y et al. 1987 (J Antibiot, 40(8): 1092-100)Micromonospora sp. Sch 37137 Diamino Cooper R et al. 1988 (J Antibiot, 41(1): 13-9)Micromonospora sp. Sibanomicin Pyrrole- Benzodiazepines Itoh J et al. 1988 (J Antibiot, 41(9): 1281-4)M. purpureochromogenes Crisamicin C Naphthoquinones Russell WL et al. 1988 (J Antibiot, 41(2): 149-56)M. neihuensis Neihumicin Pyrazines Wu RY et al. 1988 (J Antibiot, 41(4): 494-501)M. echinospora Calicheamicin beta1‚a‚’ Aminoglycoside Lee MD et al. 1989 Calicheamicin gamma 1‚a‚’ (J Antibiot, 42(7): 1070-87) Calicheamicin alpha2I Calicheamicin alpha3I & Calicheamicin beta1I Calicheamicin gamma1I & Calicheamicin ƒÂ1I M. echinospora Calicheamicins Aminoglycoside Maiese WM et al. 1989 (J Antibiot, 42(4): 558-63)M. citrea LL-E19085 alpha Oxazoles Maiese WM et al. 1989 (J Antibiot, 42(6): 846-51)M. chersina Dynemicin A Anthraquinones Konishi M et al. 1989 (J Antibiot, 42(9): 1449-52)M. greseorubida Mycinamicin VIII Macrolide Kinoshita K et al. 1989 (J Antibiot, 38(4): 522-6)M. globosa Dynemicin A, deoxy- Anthraquinones Shiomi K et al. 1990 (J Antibiot, 43(8): 1000-5)M. citrea Citreamicins Oxazoles Carter GT et al. 1990 (J Antibiot, 43(5): 504-12)M. fastidiosa 6108 A1, B, C & D Macrolide Funaishi K et al. 1990 (J Antibiot, 43(8): 938-47)M. globosa Megalomicin Macrolide Shiomi et al. 1990 (J Antibiot, 43(8): 1000-5)Micromonospora sp. Trehazolin Disaccharide Ando O et al. 1991 (J Antibiot, 44(10): 1165-8)M. chersina Dynemicin O, P & Q Anthraquinones Miyoshi-Saitoh M et al. 1991 (J Antibiot, 44(10): 1037-44)M. greseorubida Mycinamicin X & XI Macrolide Kinoshita K 1991 (J Antibiot, 44(11): 1270-3)M. chersina Dynemicin L, M, & N Anthraquinones Konishi M et al. 1991 (J Antibiot, 44(12): 1300-5)M. greseorubida Mycinamicin IX, XII, XIII, Macrolide Kinoshita K et al. XIV, XV, XVI, XVII, XVIII 1992 (J Antibiot, 45(1): 1-9)Micromonospora sp. Trehalamine Oxazoles Ando O et al. 1993 (J Antibiot, 46(7): 1116-25)Micromonospora sp. Quinolidomicin A1, A2 & B1 Macrolide Hayakawa Y et al. 1993 (J Antibiot, 46(10): 1563-9)M. carbonaceae AC6H Aminoglycoside Shimotohno KW 1993 (J Antibiot, 46(4): 682-6)M. purpurea Gentamicin Aminoglycoside Lancini & Lorenzetti 1993 (Biotechnology of antibiotics and other

bioactive microbial metabolites (pp. 49–57))Micromonospora sp. Cororubicin Anthracycline Ishigami K 1994 (J Antibiot, 47(11): 1219-25)M. chalcea Macquarimicin A, B, and C Macrolide Jackson M et al. 1995 (J Antibiot, 48(6): 462-6)

(Continued)

Table 1. (Continued).

Cri

tical

Rev

iew

s in

Bio

tech

nolo

gy D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y In

dian

Ins

titut

e of

Tec

hnol

ogy

New

Del

hi o

n 05

/18/

12Fo

r pe

rson

al u

se o

nly.

Page 8: Rare Actino

114 K. Tiwari and R. K. Gupta

Critical Reviews in Biotechnology

Organism Antibiotic Class of compound ReferenceMicromonospora sp. Korkormicins Depsipeptide Lam et al. 1995 (J Ind Microbiol Biotechnol, 15(1): 60-5)Micromonospora sp. Rakicidin A & B Lipopeptides McBrien KD et al. 1995 (J Antibiot, 48(12): 1446-52)Micromonospora sp. MS-444 Naphthols Nakanishi S et al. 1995 (J Antibiot, 48(9): 948-51)Micromonospora sp. Pyrrolosporin A Macrolide Lam KS et al. 1996 (J Antibiot, 49(9): 860-4)Micromonospora sp. Antascomicin A, B, C, D & E Polyenes Fehr T et al. 1996 (J Antibiot, 49(3): 230-3)Micromonospora sp. BU-4664L Dibenzazepines Ohkuma and Kobaru 1996 (U.S. Pat. 5,541,181)Micromonospora sp. Thiocoraline Depsipeptides Romero F et al. 1997 (J Antibiot, 50(9): 734-7)Micromonospora sp. Crisamicin A, 9-hydroxy Naphthoquinone Yeo WH et al. 1997 (J Antibiot, 50(7): 546-50)Micromonospora sp. Cymbimicin A and B Lactone Fehr T et al. 1997 (J Antibiot, 50(11): 893-9)M. echinospora YM-47515 Isonitrile Sugawara et al. 1997 (J Antibiot, 50(11): 944-8)Micromonospora sp. Rustmicin, 21-hydroxy- Macrolides Harris GH et al. 1998 Galbonolide B, 21-hydroxy- (J Antibiot, 51(9): 837-44)M. carboncea Sch 40832 Thiostrepton- type

antibioticPuar et al. 1998

(J Antibiot, 51(2): 221-4)Micromonospora sp. Rustmicin Macrolides Sigmund & Hirsch 1998 (J Antibiot, 51(9): 829-36)Micromonospora sp. 1-Hydroxy- Crisamicin Naphthoquinone Yeo et al. 1998 GTRI-02 Unknown structure (J Antibiot, 51(10): 952-3)M. carboncea SCH-27899 (Ziracin) Oligosaccharide Foster et al. 1999 (Pharmacotherapy, 19: 1111–1117)M. coerulea Streptimidone Glutarimide Kim B S 1999 (J. Agric. Food Chem., 47(8): 3372–3380)M. polytrota Bravomicins A (I), B, C, D, Unidentified Shu Yue-Zhong et al. 1999E & F (US 99-262693 19990304)Micromonospora sp. Macquarimicin A Macrolide Tanaka M et al. 1999 (J Antibiot, 52(7): 670-3)Micromonospora sp. Staurosporine, 5’-hydroxy Carbazoles Hernández LM et al. 2000 Staurosporine, 4’-N-methyl-5’-hydroxy (J Antibiot, 53(9): 895-902)Micromonospora sp. IB-96212 Macrolide Fernández-Chimeno RI et al. 2000 (J Antibiot, 53(5): 474-8)Micromonospora sp. SB-219383 Furans Stefanska AL et al. 2000 (J Antibiot, 53(4): 345-50)Micromonospora sp. Arisostatin A and B Macrolide Furumai T et al. 2000 (J Antibiot, 53(3): 227-32)M. purpurea Unidentified Compound Polycyclic aromatic Rusnak K et al. 2001 (Appl. Microbiol. Biotechnol., 56(3-4), 502-3)Micromonospora sp. Kosinostatin Quinocycline Furumai et al. 2002 (J Antibiot, 55(2): 128-33)Micromonospora sp. GTRI-BB Naphthoquinone Yeo WH et al. 2002 (J Antibiot, 55(5): 511-5)Micromonospora sp. Streptonigrin (I) & 7-(1-methyl-

2-oxopropyl) streptonigrin (II)Quinone Wang Haishan et al. 2002

(J. Nat. Prod., 65: 721-4)Micromonospora sp. R176502 Macrolide Laakso JA et al. 2003 (J Antibiot, 56(11): 909-16)

(Continued)

Table 1. (Continued).

Cri

tical

Rev

iew

s in

Bio

tech

nolo

gy D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y In

dian

Ins

titut

e of

Tec

hnol

ogy

New

Del

hi o

n 05

/18/

12Fo

r pe

rson

al u

se o

nly.

Page 9: Rare Actino

Rare actinomycetes: a potential storehouse for novel antibiotics 115

© 2012 Informa Healthcare USA, Inc.

Organism Antibiotic Class of compound ReferenceM. echinospora Echinosporamicin (I) Polycyclic aromatic

compound with a piperazinone moiety

He H et al. 2004

(Helvetica Chimica Acta, 87: 1385-1391)Micromonospora sp. Manzamine A & 8-hydroxy-

manzamine Aβ-carboline alkaloid

antibioticHill R.T. et al. 2004

(PCT Int. Appl., WO 2004013297)Micromonospora sp. Micromonomycin Anthracycline Yang et al. 2004 (J Antibiot, 57(9): 601-4)Micromonospora sp. Micromonosporin A Polyene lactam macrolide Thawai et al. 2004 (Chem Biodivers, 1: 640-645)Micromonospora sp. 9-hydroxy-Crisamicin A Isochromaquinone Yoon et al. 2004 (Biochemical & Biophysical Research

Communications, 319(3): 859-865)Micromonospora sp. Retymicin Angucyclines Antal et al. 2005 Galtamycin B Anthracyclines (J Antibiot, 58(2): 95-102) Saquayamycin Z Angucyclines RibofuranoSyl-lumichrome Riboflavines M. lupini Lupinacidins A (1) & B (2) Anthraquinones Igarashi et al. 2007 (Bioorg Med Chem Lett, 17(13): 3702-5)M. carbonacea Neorustmicin Macrolide Lian Y. et al. 2007 (Chinese Journal of Antibiotics, 32(11))M. rifamycinica Rifamycin S Ansamycins Huang H. Et al. 2009 (Antonie van Leeuwenhoek, 95: 143–148)Micromonospora sp. FW03-1149 Unidentified Nie Yilei et al. 2009 (China National Offshore Drugs (1))M. rosaria 23-O-mycinosyl-20-dihydro-

rosamicinRosamicin analogue Yojiro Anzai et al. 2010

(J Antibiot, 63: 325-328)D. salmoneum 44161 Polycyclic ether Celmer et al. 1978 (U.S. Pat. No. 4,081,532)D. matsuzakiensis SF-2052 Amino glycoside Inouye et al. 1979 (J Antibiot, 32(12): 1355-6)D. matsuzakiensis Dactimicin Amino glycoside Shomura T et al. 1980 (J Antibiot, 33(9): 924-30)D. thailandense G-367 S1 Amino glycoside Satoi S et al. 1983 (J Antibiot, 36(1): 1-5)D. aurantiacum SF-2185 Azetidines Matsumoto K et al. 1985 (J Antibiot, 38(11): 1487-93)D. roseum SF-2107 Unknown structure Shomura et al. 1985 (Sci. Rep. Meiji Seika Kaisha, 24: 5-16)D. aurantiacum Tiacumicin A, B, C, D, E & F Macrolides Theriault RJ et al. 1987 (J Antibiot, 40(5): 567-74)Dactylosporangium sp. AC7230 Polyether Yaginuma S et al. 1987 (J Antibiot, 40(2): 239-41)Dactylosporangium sp. Sch 34164 Polyketide Patel M et al. 1987 (J Antibiot, 40(10): 1414-8)Dactylosporangium sp. Dactylocyclines A & B Polyketide Wells JS et al. 1992 (J Antibiot, 45(12): 1892-8)D. aurantiacum Tiacumicins, bromo Macrolides Hochlowski JE et al. 1997 (J Antibiot, 50(3): 201-5)Dactylosporangium sp. SF2809 compounds Unknown structure Tani M et al. 2004 (J Antibiot, 57(2): 83-8)D. aurantiacum OPT-80 Macro cyclic Johnson Alan P 2007 (Curr Opin Investig Drugs., 8(2): 168-73)Salinispora strain Salinosporamide A Lactone Feling et al. 2003 (Angew Chem Int Ed Engl, 42(3): 355-357)

(Continued)

Table 1. (Continued).

Cri

tical

Rev

iew

s in

Bio

tech

nolo

gy D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y In

dian

Ins

titut

e of

Tec

hnol

ogy

New

Del

hi o

n 05

/18/

12Fo

r pe

rson

al u

se o

nly.

Page 10: Rare Actino

116 K. Tiwari and R. K. Gupta

Critical Reviews in Biotechnology

Organism Antibiotic Class of compound ReferenceSalinispora pacifica Cyanosporasides A & B Diene Glycosides Oh Dong-Chan et al. 2006 (1& 2) (Org. Lett., 8(6): 1021-4)Salinispora strain Rifamycins Ansamycins Kim TK et al. 2006 (Appl Environ Microbiol, 72(3): 2118-25)Salinispora arenicola Saliniketals A & B Bicyclic Polyketide Williams et al. 2007 (J Nat Prod, 70(1): 83-8)Salinispora arenicola Arenicolides A-C (1-3) Polyketide Williams et al. 2007 (J. Org. Chem., 72(14): 5025-34)Salinispora tropica Salinilactam A Polyene macrolactum Udwary DW 2007 (Proc. Natl. Acad. Sci., 104(25): 10376–10381)Salinispora pacifica Salinipyrones A & B (1, 2) Polyketide Oh Dong-Chan et al. 2008 Pacificanones A & B (3, 4) (J Nat Prod, 71(4): 570-5)Salinispora tropica Sporolides A & B (1) Polycyclic macrolides McGlinchey 2008 (J. Am. Chem. Soc., 130: 2406-2407)Salinispora arenicola Cyclomarazines A & B Peptide Schultz et al. 2008 Cyclomarin D (J. Am. Chem. Soc., 130(13): 4507–4516)Salinispora arenicola Arenimycin Benzo[α] naphthacene Asolkar et al. 2010

Quinone derivatives (J Antibiot, 63(1): 37–39)Verrucosispora strain Abyssomicin B, C & D Polycyclic polyketide Bister et al. 2004 (Angew Chem Int Ed Engl, 43(19): 2574-2576)Verrucosispora strain Abyssomicins Polycyclic polyketide Riedlinger et al. 2004 (J Antibiot, 57: 271-279)Verrucosispora strain Abyssomicins G & H Polycyclic polyketide Keller S et al. 2007a Atrop-abyssomicin C (J Antibiot, 60(6): 391-394)Verrucosispora strain Proximicin A, B & C Aminofuran Fiedler et al. 2008 (J Antibiot, 61(3): 158-63)V. sediminis Unidentified Cyclodipeptide Dai H-Q et al. 2010 (Int J Syst Evol Microbiol (in press))V. maris Atrop-abyssomicin C Polycyclic polyketide Goodfellow et al. 2010a (Int J Syst Evol Microbiol (in press))Verrucosispora gifhornensis Gifhornenolones A (1) & B (2) Terpenoids Shirai M et al. 2010 (J Antibiot, 63: 245–250)A. brasiliensis A/672 Unknown structure Thiemann et al. 1969 (J Antibiot, 22: 119-125)A. missouriensis Actinomycin monolactone Lactone Rickards RW et al. 1973 (J Antibiot, 26(3): 177-8)A. ianthinogenes Purpuromycin Naphthoquinone Coronelli et al. 1974 (J Antibiot, 27: 161-168)A. deccanensis Lipiarmycin Macrolide Parenti 1975 (J Antibiot, 28(4): 247-252)Actinoplanes sp. Sch 16656 Polyene GH Wagman 1975 (Antimicrob Agents Chemother, 7(4): 457-61)A. garbadinensis Gardimycin Peptide Parenti et al. 1976 (J Antibiot, 29(5): 501-6)A. philippinensis A2315 Polyene Chamberlin JW et al. 1977 A2315A Cyclic Polypeptide (J Antibiot, 30(3): 197-201)A. teichomyceticus Teicoplanin Glycopeptide Bardone et al. 1978 Teichomycin A1 Phosphoglycolipid (J Antibiot, 31(3): 170-7) Teichomycin A2 Glycopeptide Actinoplanes sp. A-10947 Peptide Yaginuma S et al. 1979 (J Antibiot, 32(9): 967-9)Actinoplanes sp. A 17002 C Cyclic Polypeptide Martinelli et al. 1979 (J Antibiot, 32(2): 108-14)A. utahensis Steffimycin, 10-dihydro Naphthacene Wiley PF et al. 1980 Steffimycin B, 10-dihydro (J Antibiot, 33(8): 819-23)A. philipinensis Hematinic acid, iso Succinimides Takeuchi et al. 1983

(Continued)

Table 1. (Continued).

Cri

tical

Rev

iew

s in

Bio

tech

nolo

gy D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y In

dian

Ins

titut

e of

Tec

hnol

ogy

New

Del

hi o

n 05

/18/

12Fo

r pe

rson

al u

se o

nly.

Page 11: Rare Actino

Rare actinomycetes: a potential storehouse for novel antibiotics 117

© 2012 Informa Healthcare USA, Inc.

Organism Antibiotic Class of compound Reference (J Antibiot, 36(5): 493-496)A. awajinensis Mycoplanecins Peptide Torikata A et al. 1983 (J Antibiot, 36(8): 957-960)A. awajinensis Mycoplanecin A Peptide Nakajima M et al. 1983 (J Antibiot, 36(8): 961–966)A. teichomyceticus Teichomycin T-A 2-1 Glycopeptide Borghi A et al. 1984 Teichomycin T-A 2-2, Teichomycin T-A 2-3 (J Antibiot, 37(6): 615-20) Teichomycin T-A 2-4, Teichomycin T-A 2-5 & Teichomycin T-A 3Actinoplanes sp. A-16686 Polypeptide Cavalleri B et al. 1984 (J Antibiot, 37(4): 309-17)A. missouriensis Actaplanin Glycopeptides Debono M 1984 (J Antibiot, 37(2): 85-95)A. missouriensis Actaplanin bromine analogs Glycopeptide Huber FM et al. 1988 (J Antibiot, 41(6): 798-801)Actinoplanes sp. Actinoplanones A (1), B (2) Polycyclic Xanthones Kobayashi K et al. 1988 Actinoplanones C, D, E, F & G (J Antibiot, 41: 502–11)A. deccanensis Lipiarmycin B3 & B4 Aminoglycosides Cavalleri B et al. 1988 (J Antibiot, 41(3): 308-15)Actinoplanes sp. Ramoplanin Lipoglycodepsipeptide Ciabatti & Cavalleri 1989 (Eur. Patent EP337203)A. teichomyceticus RS (1-4) Glycopeptide Borghi A et al. 1989 (J Antibiot, 42(3): 361-6)Actinoplanes sp. Immunomycin desmethyl & Piperidines Chen TS et al. 1992 FK506 desmethyl derivatives (J Antibiot, 45(1): 118-23)Actinoplanes sp. Sch 42137 Xanthones Cooper R et al. 1992 (J Antibiot, 45(4): 444-53)Actinoplanes sp. A-16686 A1, A2 & A3 Lipoglycodepsipeptide Gastaldo et al. 1992 Complex (J Ind Microbiol., 11(1): 13-8)Actinoplanes sp. Rapamycin Analogs Polyenes Nishida H et al. 1995 (J Antibiot, 48(7): 657-66)Actinoplanes sp. Cyclosporin A derivatives Cyclosporine Kuhnt M et al. 1996 (J Antibiot, 49(8): 781-7)Actinoplanes sp. Acarbose-7-phosphate Trisaccharides Goeke K 1996 (J Antibiot, 49(7): 661-3)A. teichomyceticus Teicoplanin- like antibiotic Glycopeptide Quarta C et al. 1996 (J Antibiot, 49(7): 644-50)Actinoplanes sp. BE-40644 Benzoquinone Torigoe K et al. 1996 (J Antibiot, 49(3): 314-7)Actinoplanes sp. A-21459 (A&B) Cyclic Peptide Selva E et al. 1996 (J Antibiot, 49(2): 150-4)Actinoplanes sp. Sch 54445 Polycyclic Xanthone Chu M et al. 1997 (J Nat Prod, 60(5): 525-8)A. teichomyceticus Teicoplanin, 4, 7- decadienoyl- Glycopeptide Lazzarini et al. 1997 Teicoplanin,

4-hydroxy- decanoyl- (J Antibiot, 50(2): 180-3)

A. ianthinogenes 7, 8-dideoxy-6-oxo-griseorhodin C

Hydroquinone Panzone G et al. 1997

(J Antibiot, 50(8): 665-70)Actinoplanes sp. Mathemycin A Macrolide Mukhopadhyay T et al. 1998 (J Antibiot, 51(6): 582-5)A. brasiliensis A-3802 Complex Peptide Katrukha et al. 1999 (Antibiot Khimioter, 44(5): 6-11)Actinoplanes sp. BE-40665D Unknown Structure Tsukamoto et al. 1999 (J Antibiot, 52(2): 178-81)A. liguriae Actagardine, ala (0)- Peptide Vértesy L et al. 1999 (J Antibiot, 52(8): 730-41)

(Continued)

Table 1. (Continued).

Cri

tical

Rev

iew

s in

Bio

tech

nolo

gy D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y In

dian

Ins

titut

e of

Tec

hnol

ogy

New

Del

hi o

n 05

/18/

12Fo

r pe

rson

al u

se o

nly.

Page 12: Rare Actino

118 K. Tiwari and R. K. Gupta

Critical Reviews in Biotechnology

that an average actinomycete strain has the genetic potential to produce 10~20 secondary metabolites (Bentley et al., 2002; Omura et al., 2001; Sosio et al., 2000). Although, a single isolate may have the genetic potential to synthesize more than one secondary metabolite, the probability of discovering a novel compound can be far greater if unique isolates are screened simultaneously. Thus, a new collection of novel microorganisms becomes an essential prerequisite.

Among all known antibiotics, the frequency distri-bution of the most common ones far exceeds the dis-tribution of the least known antibiotics. More than 107 actinomycetes need to be screened to find a single new antibiotic, besides the other well-known ones whose abundance is below this threshold (Baltz, 2007). This is a major challenge in the path of discovery of novel antibiotics as others that are far more common and already known antibiotics also appear among these searches at high frequencies. These antibiotics need to be weeded out first as part of any new antibiotic screen-ing process.

In recent years, one of the most striking characteristics and a little surprising feature has been the declining rep-resentation of the earlier intensively investigated genera of actinomycetes. Presently, their share among all known microbial products is only 30~35%, in contrast with the 75~80% of their share during the 1960s to 1980s (Tishkov, 2001).

During the past 50 years, only the “tip of the iceberg” of actinomycetes have been isolated from soil and their antibiotic products sampled (Baltz, 2005; Watve et al., 2001). Antibiotics not yet discovered are more likely to be produced from random actinomycetes at a frequency of ≤1 in 107 in their fermentation broths (Baltz, 2005; Baltz, 2007). The probability of obtaining different metabolites can be increased by fermenting various strains in place of repeated fermentation of the same strain (Donadio et al., 2002).

Since the last two decades, non-streptomycete actinomycetes (rare actinomycetes) have increased sig-nificantly up to a 25~30% share of all known antibiotics (Tishkov, 2001). Given this, the probability of finding a new compound of economic significance using conven-tional methodologies of microbial isolation and assay is

remote. Search efforts for finding organisms producing novel antibiotics require either high-throughput screen-ing or specific sampling methods or selections that enrich the unexamined subsets of actinomycetes.

In the past, screening collections of these organisms have been assembled almost randomly with little prior knowledge of the microbial diversity in the material being sampled (Perić-Concha and Long, 2003). The role of rare actinomycetes as prolific producers of bioac-tive molecules is evident from the estimates that these organisms have provided about 25% of the antibiotics of actinomycete origin reported during 1975 to 1980 (Nisbet, 1982).

The relevance of the rare actinomycetes in this regard can also be demonstrated by the fact that many of the successful antimicrobial agents currently available in the market are produced by them. For example, rifa-mycins are produced by Amycolatopsis mediterranei, erythromycin by Saccharopolyspora erythraea, teico-planin by Actinoplanes teichomyceticus (Table 1), van-comycin by Amycolatopsis orientalis, and gentamicin from Micromonopsora purpurea (Table 1) (Lancini and Lorenzetti, 1993). Table 1 shows the chronological sequence of antibiotic compounds discovered as prod-ucts of Micromonospora and Actinoplanes spp.

Among the rare actinomycetes the genus Streptosporangium is less exploited. A relatively low number of strains of this genus have been exploited in comparison to Actinoplanes, Micromonospora, Streptomyces, and other actinomycetes strains. It has also been found that Streptosporangium strains can pro-duce valuable substances of biological interest (Cooper et al., 1990; Lazzarini et al., 2001; Pfefferle et al., 2000). Such results emphasize the need to continue research in this area. Table 2 shows the chronological sequence of antibiotic compounds discovered as products of Streptosporangium spp. These compounds belong to a broad spectrum of diverse chemical classes, making the members of this genus very attractive to industrial screening programmers.

Eventually, the focus of industrial screening has also shifted to the members of other lesser-exploited prolific groups of rare actinomycetes such as Actinomadura, Amycolatopsis, Dactylosporangium, Kibdelosporangium,

Organism Antibiotic Class of compound ReferenceA. friuliensis Friulimicin A, B, C & D Lipopeptide Aretz W et al. 2000 (J Antibiot, 53(8): 807-15)A. capillaceus Naphthoquinone, 2-hydroxy- Naphthoquinones Fukami A et al. 2000 ethyl-3-methyl-1, 4 (J Antibiot, 53(10): 1212-4)A. friuliensis Friulimicin Lipopeptide Vertesy L 2000 (J Antibiot, 53(8): 816-27)A. utahensis Aculeacin A acylase Unknown structure Torres-Bacete et al. 2007 (Appl Environ Microbiol., 73(16): 5378-81)Actinoplanes sp. 7, 8-dihydroxy-1-methyl- Isofuranonaphthoquinone Zhang Q et al. 2009 naphtho[2,3-c]furan-4,9-dione (J Nat Prod, 72(6): 1213-5)

Table 1. (Continued).

Cri

tical

Rev

iew

s in

Bio

tech

nolo

gy D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y In

dian

Ins

titut

e of

Tec

hnol

ogy

New

Del

hi o

n 05

/18/

12Fo

r pe

rson

al u

se o

nly.

Page 13: Rare Actino

Rare actinomycetes: a potential storehouse for novel antibiotics 119

© 2012 Informa Healthcare USA, Inc.

Table 2. Diversity of antibiotic compounds discovered as products of Streptosporangium spp. The data is of the Biosearch Italia proprietary database on antibiotics from natural sources (ABL) (Lazzarani, 2001; Website (http://www.namazu.org/)).Organism Antibiotic Class of compound ReferenceS. viridogriseus Sporaviridin Glycosidic, hygromycin A - type Okuda et al. 1966 (J Antibiot, 19(2): 85-7)S. albidum Sporaviridin- like substance Unknown structure Furumai T 1968 (J Antibiot, 21(2): 85-90)S. sibiricum Sibiromycin Benzodiazepine, Gauze G.F et al. 1969 anthramycin-type (Antibiotiki, 14(11): 963-9)S. brasiliense Selenomycin Unknown structure Coronelli & Thiemann 1969 (German Patent 2,028,986)S. viridogriseum var. kofuense Chloramphenicol Alkyl-benzene derivative Tamura et al. 1971 (J Antibiot, 24: 270)Streptosporangium sp. Carminomycin I Anthracycline, daunomycin -type Brazhnikova et al. 1973 (Antibiotiki, 18(8): 678-81)S. violaceochromogenes Victomycin Glycopeptide, bleomycin- type Takasawa S et al. 1975 (J Antibiot, 28(5): 366-71)S. violaceochromogenes Platomycin A & B Glycopeptide, bleomycin -type Takasawa et al. 1975 (J Antibiot, 28: 656–661)S. vulgare Streptosporangiomycin Sugar derivative, evernino- mycin-

typeCoronelli et al. 1975

(US Patent 3,899,396)S. vulgare Sporacuracin A&B Sugar derivative, everninomycin-

typeAtsushi et al. 1975

(Japan Patent 75,125,094)S. pseudovulgare Sporamycin Basic Protein Umezawa et al. 1976 (J Antibiot, 29: 1249–1251)Streptosporangium strain PO-357 Unknown structure Umezawa I et al. 1976 (J Antibiot, 29: 1249–1251S. cinnabarinum 43334 Peptolide, virginiamycin- Celmer et al. 1977 Type (US Patent 4,032,632)S. koreanum 43596 Peptolide, virginiamycin Celmer et al. 1977 type (US Patent 4,032,632)Streptosporangium sp. Anthracycline, Figaroic acid complex, Bradner et al. 1978 Daunomycin-type (US Patent 4,112,071)S. roseum Thiosporamycin Thiazolyl-peptide, Celmer et al. 1978 thiostrepton-type (US Patent 4,083,963)Streptosporangium sp. SS-237 Adenine glycoside Berg et al. 1979 (German Patent 27, 58, 008)S. vulgare SF-2033 Sugar-derivative, Tsuguaki et al. 1979 everninomycin-type Japan Patent 79,122,202)Streptosporangium sp. SS-48 mixture Sugar-derivative, Bischoff et al. 1981 everninomycin-type (German Patent 30, 05,696)S. fragile Fragilomycin complex Anthracycline Nash III et al. 1981 (US Patent 4,293,546)S. albidum Aculeximycin Macrolide-like Ikemoto et al. 1983 (J Antibiot, 36: 1093–1096)S. pseudovulgare KUD-PC Basic protein Umezawa & Komiyama, 1983 (Japan Patent 58,198,422)Streptosporangium sp. 1,6-dihydroxyphenazine, 1, Phenazine derivative Patel et al. 1984 6-dihydroxy-2-chlorophenazine (J Antibiot, 37: 943–948)Streptosporangium sp. DC-87 (A&B) Anthracycline steffimycin- Tomita et al. 1985 Type (Japan Patent 60, 001,152)Streptosporangium sp. AI-RC 262 Oligopeptide, netropsin-like Sato et al. 1987 (Japan Patent 62,029,987)Streptosporangium sp. SF-2381 (A&B) Macrolide-like Ito et al. 1987 (Japan Patent 62,040,293)S. nondiastaticum SF-2513 (A&B&C) Oligopeptide Shokichi et al. 1988

(Continued)

Cri

tical

Rev

iew

s in

Bio

tech

nolo

gy D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y In

dian

Ins

titut

e of

Tec

hnol

ogy

New

Del

hi o

n 05

/18/

12Fo

r pe

rson

al u

se o

nly.

Page 14: Rare Actino

120 K. Tiwari and R. K. Gupta

Critical Reviews in Biotechnology

Organism Antibiotic Class of compound Reference (Meiji Seika Kenkyu Nenpo, 27:

46–54)S. carneum A-84575 complex Glycopeptide, ristocetin-type Michel & Yao, 1991 (EP 0424051)S. roseum Sporangirosomycin Peptolide Ghazal S.A. & Abl El- Aziz 1993 (Al-Azhar Bull. Sci., 4: 265–274)S. roseum WS-79089 complex Quinone-type Tsurumi et al. 1994 (J Antibiot, 47: 619–630)S. amethystogene TAN-1511 complex Lipopeptide Takizawa et al. 1995 (J Antibiot, 48: 579–588)Streptosporangium sp. K4610422 Diterpene Sugano et al. 1997 (Japan Patent 92,21,448)S. cinnabarinum 1-hydroxy-4-meth- Naphthalene derivative Pfefferle et al. 1997 oxy-2-naphthoic acid (J Antibiot, 50: 1067–1068)S. roseum AH7 Ansa-macrolactum, Hacene et al. 1998 maytansin-type (Microbios, 96: 103–109)Streptosporangium sp. Unidentified Glycosylated aromatics Boudjella H et al. 2006 (Microbiol Res, 161(4): 288-298

)S. cinnabarinum GE82832 Peptide Brandi L et al. 2006 (RNA, 12(7): 1262-1270)Streptosporangium sp. Unidentified Quinone-anthra-cycline Boudjella H et al. 2007 Aromatics (Journal of Applied

Microbiology, 103(1): 228-236)Streptosporangium sp. Unidentified Macrolactum Peoples A et al. 2009 (PCT Int.

Appl.)

(Continued)

Table 3. Diversity of antibiotic compounds discovered as products of Actinomadura spp. (Website (http://www.namazu.org/)).Organism Antibiotic Class of compound ReferenceA. pelletieri Prodigiosin, undecyl Pyrroles Gerber NN 1971 Prodiginine, methylcyclodecyl (J Antibiot, 24(9): 636-40)A. carminata Carminomycin Anthracycline Gauze GF et al.1973 (Antibiotiki, 18(8): 675-8)A. roseovilladea var. rubescens AB-64 Phenolic Tamura A et al. 1973 (J Antibiot, 26(9): 492-500)A. pusilla Actinotiocin Peptide Tamura et al. 1973 (J Antibiot, 26: 343-350)A. rubra Maduramycin Unknown structure Fleck W F et al. 1978 (Z Allg Mikrobiol., 18(6): 389-98)Actinomadura sp. Adenosine, 2’-amino-2’- Deoxyadenosines Matsuyama K et al. 1979 deoxy (J Antibiot, 32(12): 1367-9)A. macra CP-47,433 & Polycyclic ether Tone J et al. 1980 CP-47,434 (Proc. 11th Intl. Congress of

Chemotherapy)A. luzonensis BBM-928 A, B and C Quinolines Ohkuma H et al. 1980 (J Antibiot, 33(10): 1087-97)Actinomadura sp. Baumycinol A1, 4-hydroxy Unknown structure Matsuzawa Y et al. 1981 Baumycinol A2, 4-hydroxy (J Antibiot, 34(6): 774-6) Baumycin A1, 4-hydroxy Baumycin A2, 4-hydroxy A. roseoviolacea var. biwakoensis nov. var.

Rubeomycin A and A1 Anthracyclines Ogawa Y et al. 1981

Rubeomycin B and B1 (J Antibiot, 34(8): 938-50)A. kijaniata Kijanimicin Aminoglycosides Waitz JA et al. 1981

Table 2. (Continued).

Cri

tical

Rev

iew

s in

Bio

tech

nolo

gy D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y In

dian

Ins

titut

e of

Tec

hnol

ogy

New

Del

hi o

n 05

/18/

12Fo

r pe

rson

al u

se o

nly.

Page 15: Rare Actino

Rare actinomycetes: a potential storehouse for novel antibiotics 121

© 2012 Informa Healthcare USA, Inc.

Organism Antibiotic Class of compound Reference (J Antibiot, 34(9): 1101-6)A. roseoviolacea Carminomycin, N-formyl- Anthracyclines Nakagawa M et al. 1983 13-dihydro (J Antibiot, 36(4): 457-8)A. azurea nov. sp. Cationomycin Polyether Nakamura G 1983 (J Antibiot, 36(11): 1468-72)Actinomadura sp. PD 114,759 & PD 115,028 Unknown structure Bunge RH et al. 1984 (J Antibiot, 37(12): 1566-71)A. recticatena Unknown Quinone Gauze et al. 1984 (Antibiotiki, 29(1): 3-7)Actinomadura sp. SF-2140 Unknown structure Ito T et al. 1984 (J Antibiot, 37(8): 931-934)Actinomadura sp. I5B2 Phosphopeptide Kido Y et al. 1984 (J Antibiot, 37: 965–69)Actinomadura sp. Oxanthromicin Anthracene Patel M et al. 1984 (J Antibiot, 37(4): 413-5)A. roseoviolacea Akrobomycin Anthracyclines Imamura K et al. 1984 (J Antibiot, 37(1): 83-4)A. madurae simaoensis LL-D42067α (I) Unknown structure Labeda DP et al. 1985

& LL-D42067ß (II) (Eur. Pat. Appl.)A. pulveracea FR-900405 & FR-900406 Unknown structure Kiyoto S et al. 1985 (J Antibiot, 38(7): 840-8)Actinomadura sp. Adechlorin Nucleosides Omura S et al. 1985 (J Antibiot, 38(8): 1008-15)A. roseoviolaceus var. miuraensis nov. var

SN-07 Anthracyclines Kikuchi Y et al. 1985

(J Antibiot, 38(12): 1670-6)A. roseoviolacea Rhodomycinone, 4-O-(beta Anthracyclines Nakagawa M et al. 1985 -D-glucopyranosyl)-ipsilon- (J Antibiot, 38(11): 1622-4)Actinomadura sp. SF-2370 Carbazoles Sezaki M et al. 1985 (J Antibiot, (10): 1437-9)Actinomadura sp. 2’-Chloropentostatin Nucleoside Tunac JB 1985 (J Antibiot, 38(10): 1344-9)A. verrucosospora PD 119,707, PD 114,759 Unknown structure Tunac JB et al. 1985 PD 119,193 & PD 115,028 (J Antibiot, (10): 1337-43)A. oligospora Unknown Polyether P Frederick Mertz 1986 (Int J Syst Bacteriol, 36: 179-182)A. routienii Huang sp. nov. CP-54883 Polycyclic ether Cullen et al. 1987 (J Antibiot, 40(11): 1490-5)A. brunnea Sch 33256 (I) Polyketide Patel M et al. 1987 (J Antibiot, 40(10): 1408-13)Actinomadura sp. DC92-B Anthraquinones Takahashi I et al. 1988 (J Antibiot, 41(8): 1151-3)Actinomadura sp. Barminomycins I and II Anthracyclines Uchida T et al. 1988 (J Antibiot, 41(3): 404-8)A. melliaura AT2433-A1, A2, B1, B2 Aminoglycosides Matson JA et al. 1989 (J Antibiot, 42(11): 1547-55)A. pelletieri MM 46115 Macrolides Ashton RJ et al. 1990 (J Antibiot, 43(11): 1387-93)A. verrucosospora BMY40660 & BMY40662 Phenolics Beutler JA et al. 1990 (J Antibiot, 43(1): 107-9)Actinomadura sp. CP-82,996 Polyether Dirlam JP et al. 1990 (J. Ind. Microbiol., 6(2): 135-42)Actinomadura sp. CP-84,657 Polyether Dirlam JP et al. 1990 (J Antibiot, 43(6): 668-79)A. madurae Simaomicin Isoquinolines Maiese WM et al. 1990 (J Antibiot, 43(9): 1059-63)

(Continued)

Table 3. (Continued).

Cri

tical

Rev

iew

s in

Bio

tech

nolo

gy D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y In

dian

Ins

titut

e of

Tec

hnol

ogy

New

Del

hi o

n 05

/18/

12Fo

r pe

rson

al u

se o

nly.

Page 16: Rare Actino

122 K. Tiwari and R. K. Gupta

Critical Reviews in Biotechnology

Organism Antibiotic Class of compound ReferenceA. hibisica Pradimicins M, N, O & P Naphthacene-quinone Sawada Y et al. 1990 (J Antibiot, 43(11): 1367-74)A. hibisica Pradimicin D, E, Anthracyclines Sawada Y et al. 1990 (J Antibiot, 43(7): 771-7)A. hibisica Pradimicin FA-1, & FA-2 Anthracyclines Sawada Y et al. 1990 (J Antibiot, 43(10): 1223-9)Actinomadura sp. Kijimicin Polyether Takahashi Y et al. 1990 (J Antibiot, 43(4): 441-3)A. hibisica Pradimicin A, B, and C Anthracyclines Tomita K et al. 1990 (J Antibiot, 43(7): 755-62)A. roseorufa CP-91,243 & CP-91,244 Diglycoside Polyether Dirlam JP et al. 1991 (J Antibiot, 44(11): 1262-6)A. madurae Maduropeptin Peptides Hanada M et al. 1991 (J Antibiot, 44(4): 403-14)Actinomadura sp. Benanomicin A, dexylosyl Anthracyclines Kondo S et al. 1991 Benanomicin B, dexylosyl (J Antibiot, 44(2): 123-9) Benanomicin A, 2’-demeth . Benanomicinone, 7-methoxy Actinomadura sp. CP-82,009 Polyether Dirlam JP et al. 1992 (J Antibiot, 45(3): 331-40)A. roseorufa CP-120,509 Polyether Dirlam JP et al. 1992 (J Antibiot, 45(9): 1544-8)Actinomadura sp. Sch 38516, Sch 38518 & Macrolactams Hegde V et al. 1992 Sch 39185 (J Antibiot, 45(5): 624-32)Actinomadura sp. 3’-hydroxybenanomicin A, Unknown structure Kondo S et al. 1992 7-hydroxybenanomicin A & 7-hydroxybenanomicinone (J Antibiot, 18(6): 217-24)A. verrucosospora Pradinone II, 11-O-demethyl Anthracyclines Furumai T et al. 1993 -7-methoxy (J Antibiot, 46(3): 420-9)Actinomadura sp. BMS-181184 Anthracyclines Furumai T et al. 1993 (J Antibiot, 46(2): 265-74)A. verrucosospora Pradinone I Anthracyclines Furumai T et al. 1993 11-O-demethylpradinones I and II (J Antibiot, 46(3): 420-9) 11-O-demethyl-7-methoxypradinone II 11-O-demethylpradimicinone 11-O-demethyl-7-methoxypradimicinone II 11-O-demethylpradimicinone II (11dM-PMN II) 11-O-demethyl-6-deoxypradinone I 11dM-PMN II 7-hydroxypradimicin A Pradimicinone II and 11dM-PMN II A. verrucosospora Verucopeptin Depsipeptide Nishiyama Y et al. 1993 (J Antibiot, 46(6): 921-7)A. spinosa Pradimicins FS, FB Anthracyclines Saitoh K et al. 1993 (J Antibiot, 46(3): 398-405)A. verrucosospora Pradimicin FL, L Anthracyclines Saitoh K et al. 1993 (J Antibiot, 46(3): 387-97)A. verrucosospora Pradimicin Q Anthracyclines Sawada Y et al. 1993 (J Antibiot, 46(3): 507-10)Actinomadura sp. Thiazohalostatin Thiazoles Yamagishi Y et al. 1993 (J Antibiot, 46(11): 1633-7)A. spiralis Pyralomicins (1a, 1b, 1c & 1d)

& (2a, 2b & 2c)Benzopyrans Kawamura N et al. 1995

(J Antibiot, 48(5): 435-7)A. verrucosospora Esperamicin A1c and A2c Aminoglycosides Lam KS et al. 1995 (J Antibiot, 48(12):1497-501)A. madurae Carbazomadurins A and B Carbazoles Kotoda N et al. 1997

(Continued)

Table 3. (Continued).

Cri

tical

Rev

iew

s in

Bio

tech

nolo

gy D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y In

dian

Ins

titut

e of

Tec

hnol

ogy

New

Del

hi o

n 05

/18/

12Fo

r pe

rson

al u

se o

nly.

Page 17: Rare Actino

Rare actinomycetes: a potential storehouse for novel antibiotics 123

© 2012 Informa Healthcare USA, Inc.

Table 4. Diversity of antibiotic compounds discovered as products of Amycolatopsis spp. (Website (http://www.namazu.org/)).Organism Antibiotic Class of compound ReferenceAmycolatopsis sp. Octacosamicin A and B Guanidines Dobashi K et al. 1988 (J Antibiot, 41(11): 1533-41)A. orientalis Orienticin A, chloro Glycopeptide Tsuji N et al. 1988 Orienticin B, chloro (J Antibiot, 41(10): 1506-10) Orienticin C, chloro, Orienticin D, chloro, Orienticin E, chloroA. orientalis UK-69,753 Pyrans Pacey MS et al. 1989 (J Antibiot, 42(10): 1453-9)A. orientalis MM 47761 & MM 49721 Glycopeptide Box SJ et al. 1990 (J Antibiot, 43(8): 931-7)Amycolatopsis sp. MM 55266 & MM 55268 Glycopeptide Box SJ et al. 1991 (J Antibiot, 44(8): 807-13)A. orientalis Quartromicin (A1, A2, & A3) and

(D1, D2, & D3)Lactones Tsunakawa M et al. 1992

(J Antibiot, 45(2): 180-8)Amycolatopsis sp. Dethymicin Unknown Ueno M et al. 1992 (J Antibiot, 45(12): 1819-26)A. alba Unidentified Glycopeptide Mertz F P 1993 (Int J Syst Bacteriol, 43(4): 715-20)Amycolatopsis sp. Balhimycin Glycopeptide Nadkarni SR et al. 1994 (J Antibiot, 47(3): 334-41)Amycolatopsis sp. Amythiamicin A, B, C, & D Thiazoles Shimanaka K et al. 1994 (J Antibiot, 47(6): 668-74)Amycolatopsis sp. Ochracenomicins A, B & C Benz[a]anthraquinone Igarashi M et al. 1995 (J Antibiot, 48(4): 335-7)A. sulphurea Azicemicin A(1) & B(2) Benz (a) Anthracenes Tsuchida T et al. 1995 (J Antibiot, 48(3): 217-21)A. Amycolatopsis Quinomicin B, epoxy Quinones Tsuchida T et al. 1996Amycolatopsis sp. Quinomicin A, epoxy Quinones (J Antibiot, 49(3): 326-8)Amycolatopsis sp. Balhimycin-related Glycopeptide Vértesy L et al. 1996 Compound (J Antibiot, 49(1): 115-8)A. Xenova XR651 Naphthacenes Bahl S et al. 1997 (J Antibiot, 50(2): 169-71)Amycolatopsis sp. Epoxyquinomicin A, B, C & D Quinones Matsumoto N et al. 1997 (J Antibiot, 50(11): 900-5)

Organism Antibiotic Class of compound Reference (J Antibiot, 50(9): 770-2)Actinomadura sp. Decatromicins A and B Macrolide Momose I et al. 1999 (J Antibiot, 52(9): 781-6)Actinomadura sp. IB-00208 Polycyclic Xanthone Malet-Cascón L et al. 2003 (J Antibiot, 56(3): 219-25)Actinomadura sp. Chandrananimycin A (3c), Macrolide Maskey et al. 2003 B (3d), C (4) and Iodinin Phenazine (J Antibiot, 56(7): 622-9)Actinomadura sp. ZHD-0501 Indolocarbazole Han X et al. 2005 (Tetrahedron Lett, 46: 6137-6140)Actinomadura sp. GE23077 Cyclic heptapeptide Marazzi A. et al. 2005 (J Antibiot, 58(4): 260-7)Actinomadura sp. A104 complex Unknown structure Badji B et al. 2006 (Can J Microbiol, 52(4): 373-82)A. rubra Butylmaduramycin Maduramycin derivative Strauss DG 2007 (J. Basic Microbiol., 26(3):

169–172)A. carminata Carminomycin Anthracyclines Lapchinskaya et al. 2009 (RU 2007-115995 20070427)

(Continued)

Table 3. (Continued).

Cri

tical

Rev

iew

s in

Bio

tech

nolo

gy D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y In

dian

Ins

titut

e of

Tec

hnol

ogy

New

Del

hi o

n 05

/18/

12Fo

r pe

rson

al u

se o

nly.

Page 18: Rare Actino

124 K. Tiwari and R. K. Gupta

Critical Reviews in Biotechnology

(Continued)

Organism Antibiotic Class of compound ReferenceAmycolatopsis sp. Tigloside Tigloylated tetrasaccharide Breinholt J et al. 1998 (Acta Chemica Scandinavica,

52(10): 1239-1242)Amycolatopsis sp. Quinaldopeptin & Cyclic decapeptide Rickards RW et al. 1998 Actinotetraose hexatiglate Hexa-ester (J Antibiot, 51(12): 1093-8)Amycolatopsis sp. MJ347-81F4 (A & B) Peptides Sasaki T et al. 1998 (J Antibiot, 51(8): 715-21)Amycolatopsis sp. Spiroximicin Unknown structure Takeuchi et al. 1998 (Anti-infective Therapy, 20(9):

788)A. mediterranei Rifamycin W, 34a-deoxy Polyketide Stratmann A et al. 2002 Proansamycin B (J Antibiot, 55(4): 396-406)A. mediterranei Rifamycin SV Ansamycin Krishna PS et al. 2003 (Biotechnol Appl Biochem, 37(3):

311-5)Amycolatopsis sp. Kigamicin A, B, C, D, and E Oxazoles Kunimoto S et al. 2003 (J Antibiot, 56(12): 1004-11)Amycolata autotrophica Epothilone D, 9-hydroxy- Macrolides Tang L et al. 2003 Epothilone D, 11-hydroxy- (J Antibiot, 56(1): 16-23) Epothilone D, 14-hydroxy- & Epothilone D, 21-hydroxy- Epothilone D, 26-hydroxy- & Epothilone D, 21, 26-dihydroxy- Epothilone D, 21-hydroxy 10, 11-dehydro- & Epothilone D, 26-hydroxy 10, 11-dehydro-Amycolatopsis sp. A-102395 Nucleoside Murakami R et al. 2007 (J Antibiot, 60(11): 690-5)Amycolatopsis sp. Pargamicin A Cyclic peptide (J Antibiot, 63: 279-283)

Table 5. Diversity of antibiotic compounds discovered as products of Kibdelosporangium, Microbispora, Kitasatospora, Planomonospora, Planobispora spp. (Website (http://www.namazu.org/)).Organism Antibiotic Class of compound ReferenceKibdelosporangium aridum AAD 216 (A, B, C & D) Glycopeptides Bowie et al. 1985 (European Patent Appl., EP 132118)K. aridum Aridicins Glycopeptides Shearer et al. 1985 (J Antibiot, 38(5): 555-60)K. aridum Aridicin aglycone Glycopeptides Chung SK et al. 1986 (J Antibiot, 39(5): 652-9)K. aridum Kibdelins (A, B, C1, C2, D) Glycopeptides Shearer MC et al. 1986 (J Antibiot, 39(10): 1386-94)K. philippinensis A 80407 (A & B) Glycopeptides Doolin et al. 1989 (European Patent Appl., EP 299707)K. deccaensis Decaplanin Glycopeptide Franco et al. 1990 (European Patent Appl., EP 356894)K. albatum Cycloviracins B1 and B2 Macrolides Tsunakawa M et al. 1992 (J Antibiot, 45(9): 1467-71)Kibdelosporangium sp. Isokibdelones Polyketide Ratnayake R et al. 2006 (Org. Lett., 8(23): 5267-70)Kibdelosporangium sp. Kibdelones Polyketide Xanthone Ratnayake R et al. 2007 (Chemistry, 13(5): 1610-9)Kibdelosporangium sp. Azicemicins Angucycline-type Ogasawara Y & Liu HW 2009 (J. Am. Chem. Soc., 131(50): 18066-8)Microbispora sp. Sch 31828 Oxazoles Patel M et al. 1988 (J Antibiot, 41(6): 794-7)Microbispora sp. Cochinmicins I, II, III Peptolides Lam YK et al. 1992 (J Antibiot, 45(11): 1709-16)Microbispora sp. Angelmicin A and B Anthraquinones Uehara Y et al. 1993 (J Antibiot, 46(8): 1306-8)

Table 4. (Continued).

Cri

tical

Rev

iew

s in

Bio

tech

nolo

gy D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y In

dian

Ins

titut

e of

Tec

hnol

ogy

New

Del

hi o

n 05

/18/

12Fo

r pe

rson

al u

se o

nly.

Page 19: Rare Actino

Rare actinomycetes: a potential storehouse for novel antibiotics 125

© 2012 Informa Healthcare USA, Inc.

Organism Antibiotic Class of compound ReferenceMicrobispora sp. Propeptin Peptide Kimura K et al. 1997 (J Antibiot, 50(5): 373-8)Microbispora sp. Glucosylquestiomycin N-glucopyranoside Igarashi Y et al. 1998 (J Antibiot, 51(10): 915-20)Microbispora rosea Hibarimicin A, B, C, D & G Glycosides Kajiura T et al. 1998 (J Antibiot, 51(4): 394-401)Microbispora aerata Microbiaeratinin & Indole Alkaloid Ivanova V et al. 2007Microbiaeratinin (1a) (Prep Biochem Biotechnol, 37(2): 161-8)Microbispora sp. Propeptin-2 Peptide Kimura K et al. 2007 (J Antibiot, 60(8): 519-23)Microbispora sp. Bispolides (A1, A2, A3, Macrodiolide Okujo et al. 2007 B1, B2a, B2b & B3) (J Antibiot, 60(3): 216-9)Microbispora sp. Microbisporicin Polypeptide Castiglione F et al. 2008 (Chem Biol., 15(1): 22-31)K. setae Setamycin Macrolide Omura S et al. 1981 (J Antibiot, 34(10): 1253-6)K. phosalacinea Phosalacine Dipeptide Omura et al. 1984 (J Antibiot, 37(8): 829-35)K. griseola Terpentecin Diterpenoid Tamamura et al.1985 (J Antibiot, 38(12): 1664-9)K. setae Propioxatins Dipeptide Inaoka et al. 1986 (A & B) (J Antibiot, 39(10): 1368-77)K. kifunense FR-900494 Amino acids Iwami et al. 1987 (J Antibiot, 40(5): 612-22)K. papulosa AB-110-D Carbapenem Nakamura et al. 1988 (J Antibiot, 41(5): 707-11)K. cystarginea Cystargin Peptide Uramoto et al. 1988 (J Antibiot, 41(12): 1763-8)Kitasatospora sp. Tyrostatin Peptide Oda et al. 1989 (Agric Biol Chem, 53: 405-415)Kitasatospora sp. Tyropeptin A and B Dipeptides Momose I et al. 2001 (Biosci Biotechnol Biochem, 54:

997–1003)K. cheerisanensis Bafilomycin C1-amide Macrolides Moon SS et al. 2003 (J Antibiot, 56(10): 856-61)Kitasatospora sp. Streptonigrin & Quinone Jin Ying-Yu et al. 2005 Oxopropaline G (J. Microbiol. Biotechnol., 15(5): 1140-

1145)Kitasatospora sp. Sch 725424 & Unidentified Yang SW et al. 2005 Sch 725428 (J Antibiot, 58(3): 192-5)K. kifunense Talosins A & B Isoflavonol Glycosides Yoon TM et al. 2006 J Antibiot, 59(10): 633-9)Kitasatospora sp. Kitastatin 1, Respirantin & Cyclodepsipeptides Pettit GR et al. 2007 its valeryl homologue (J Nat Prod, 70(7): 1069-72)Planomonospora parontospora

Sporangiomycin Peptide Thiemann JE et al. 1968

var. Antibiotca (J Antibiot, 21(9): 525-31)Planomonospora sp. 97518 Peptide Losi Daniele et al. 2004 (European Patent Application

EP1481986)Planomonospora sp. Planosporicin Polyketide Castiglione et al. 2007 (Biochemistry, 46(20): 5884-95)Planobispora rosea GE2270, GE2270 A Thiazolylpeptide Selva E et al. 1991 (J Antibiot, 44(7): 693-701)Planobispora rosea GE2270 B1, GE2270 B2, Thiazolylpeptide Selva E et al. 1995 GE2270 C1, GE2270 C2a (J Antibiot, 48(9): 1039-42) GE2270 C2b, GE2270 D1, GE2270 D2, GE2270 E, GE2270 T

Table 5. (Continued).

Cri

tical

Rev

iew

s in

Bio

tech

nolo

gy D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y In

dian

Ins

titut

e of

Tec

hnol

ogy

New

Del

hi o

n 05

/18/

12Fo

r pe

rson

al u

se o

nly.

Page 20: Rare Actino

126 K. Tiwari and R. K. Gupta

Critical Reviews in Biotechnology

Microbispora, Kitasatospora, Planomonospora, Planobispora, Salinispora, and Verrucosispora spp. In this review, we have also tried to update the information on the antibiotic compounds identified from other groups of rare actinomycetes such as Actinomadura (Table 3), Amycolatopsis (Table 4), Dactylosporangium (Table 1), Kibdelosporangium, Microbispora, Kitasatospora, Planomonospora, Planobispora (Table 5), Salinispora, and Verrucosispora spp. (Table 1) and have classified them in terms of their chemical structures, covering the most recent published literature (Website (http://www.namazu.org/)). In such a scenario, the investments in rare actinomycetes can be considered as being completely warranted.

Techniques for isolation of rare actinomycetesAs the multiplication time of actinomycetes is extremely slow in comparison to other bacteria, their isolation programs take several months to complete. The meth-ods of isolating rare actinomycetes deal almost exclu-sively with those suitable for Streptomyces species, which grow rapidly on soil dilution plates. In such a case, much of our efforts will be wasted if the genera of interest are not present in the material being sampled, which can be particularly challenging while targeting rare actinomycetes (Long et al., 1994). For recovering slow-growing microorganisms, Zengler et al. (2005) described a novel method using a high-throughput system based on micro encapsulation of single cells combined with parallel microbial cultivation under low nutrient flux conditions.

According to the source and the targeted groups of microbes, different methods have to be applied for iso-lating many diverse microbes. Three approaches deserve particular attention for culturing microbes: dilution to extinction of environmental samples; low nutrient con-centrations; and virus-depleted incubation conditions (Bull and Stach, 2007). There has been a considerable increase in basic knowledge about the habitat, physiol-ogy, and productivity of the molecules from rare actino-mycetes. This has led to the discovery of their ecologically significant properties, which has made their screening sources expand into unexplored and under explored niche habitats. Apparently, these un- and under-explored habitats, such as desert biomes and marine ecosystems, are being described on a regular basis (Bredholt et al., 2008; Bull et al., 2005; Bull and Stach, 2007; Okoro et al., 2009).

Unfortunately, taxonomic relationships among them are still lacking, and as a result only a minor proportion of rare actinomycetes from natural environments have been isolated by conventional methods. Moreover, with conventional isolation techniques, most of the isolates recovered on isolation plates were identified as the genus Streptomyces (Iwai and Takahashi, 1992; Lechevalier and Lechevalier, 1967; Nolan and Cross, 1988). It is the most dominant group among the soil actinomycetes.

Rare actinomycetes are not as easy to isolate as the members of Streptomyces genera or other bacterial and

fungal organisms. Thus, the objective of an isolation pro-gram should be to obtain, with the minimum effort, as large a number as possible of microbes that are unusual and difficult to isolate. Identification of the isolates on a primary isolation plate and their initial recognition as novel taxa is of immense importance both for practical as well as for taxonomical purposes. A series of methods has already been developed that can help us in the isolation of unusual groups of microorganisms.

Various pretreatment procedures and selective isola-tion media have been used to assess the best conditions, to detect the microbial diversity in a given sample and for isolating novel and rare actinomycetes for screening. A wide variety of selective methods have been used to isolate novel strains producing new antibiotics (Lamari et al., 2002; Sabaou et al., 1998; Zitouni et al., 2004a; Zitouni et al., 2004b). Through this study we wish to reemphasize the value of deploying a wide range of pre-treatment procedures and selective isolation media for this purpose.

The pretreatment of samples collected from various natural habitats is used for the selective isolation of rare actinomycetes. Pretreatment of soil samples, by both drying and heating, stimulates the isolation of spores of rare actinomycetes (Kim et al., 1995; Nolan and Cross, 1988). For this purpose, various chemical compounds have been employed by different researchers, such as phenol (Hayakawa et al., 1991b; Nonomura, 1988) and chloramine-T (Hayakawa et al., 1997). The most prolific genus after Streptomyces is represented by the strains of the genus Actinoplanes, which have been extensively isolated by the mobility and chemotactic behavior of their spores towards different saline or organic solutions (Hayakawa et al., 1991; Palleroni, 1980).

Members of the genus Streptosporangium are dif-ficult to isolate in comparison to the other genera of rare actinomycetes by traditional isolation methods. It is because of their very slow growth on isolation media that they are unable to compete with the faster-growing actinomycetes. Some of the well known selective isola-tion procedures developed for the members of the genus Streptosporangium exploits the ability of their sporan-giospores to withstand and resist physical or chemical pretreatments. Treatments such as dry heating or micro-wave irradiation (Bulina et al., 1997; Kizuka et al., 2002), with toxic chemical agents such as benzethonium chlo-ride and chloramine-T (Hayakawa et al., 1997) or with specific antibiotics such as leucomycin and tobramycin (Hayakawa et al., 1991a) are extensively used for their selective isolation.

The application of these methods to soil samples, col-lected from different ecological niches, has led to the iso-lation of at least one strain of Streptosporangium in more than half of the treated soils (Lazzarini et al., 2001). The results clearly show that this genus is not as rare as previ-ously considered. The preliminary studies on the isola-tion of the genus Streptosporangium indicate that these strains can be successfully recovered from different soil

Cri

tical

Rev

iew

s in

Bio

tech

nolo

gy D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y In

dian

Ins

titut

e of

Tec

hnol

ogy

New

Del

hi o

n 05

/18/

12Fo

r pe

rson

al u

se o

nly.

Page 21: Rare Actino

Rare actinomycetes: a potential storehouse for novel antibiotics 127

© 2012 Informa Healthcare USA, Inc.

samples; once specific and selective isolation methods are developed and massively applied.

A wide range of physical agents, such as ultraviolet radiations (Galatenko et al., 1990), ultrasonic waves (Miquely et al., 1993), super high frequency (SHF) radia-tions (Bulina et al., 1997) have also been used for their selective isolation. The use of physical agents, such as electric pulses (Bulina et al., 1998) and thermal treat-ment (Hayakawa et al., 1991a; Li-Hua et al., 1996) has also been explored for this purpose. The possibility of employing extremely high-frequency (EHF) radiations has also been investigated for the selective isolation of rare actinomycete genera from soil (Li Yu et al., 2002a; Li Yu et al., 2002b). The results clearly show the efficiency of EHF radiation of certain wavelengths in this regard. In fact, they were the first to employ and report the suc-cessful use of EHF radiations for the selective isolation of actinomycetes.

Several antibiotic molecules have also been used with selective isolation media to inhibit the competing bacteria including fast-growing actinomycetes (Okami and Hotta, 1988). Among actinomycetes, another genus that is being exploited using this approach recently is Micromonospora. It is considered to be the second larg-est group of culturable actinomycetes in soil. They can easily be isolated with antibiotics such as gentamicin and novobiocin, as selective agents (Williams and Wellington, 1982), or chemicals like phenol and chlorhexidine glu-conate solutions (Hayakawa et al., 1991b).

Specialized growth media have also been developed to isolate specific actinomycete genera. Macromolecules such as casein, chitin, hair hydrolysate, and humic acid have been chosen and efficiently used as carbon and nitrogen sources for rare actinomycetes during their isolation (Cho et al., 1994; Hayakawa et al., 1987a; Hayakawa et al., 1987b). Recovery of rare actinomycetes needs innovative microbiology, in addition to a greater understanding of physiology and taxonomy.

Screening techniques for detection of novel secondary metabolitesSearching for new chemical entities to treat many human diseases is considered to be an expensive and tedious process and thus, big pharmaceutical compa-nies worldwide have largely abandoned natural product screening programs. One reason may be that the rate of rediscovering known metabolites remains high and the efforts required to reach this realization are significant. Furthermore, the past endeavors make the discovery of new bioactive metabolites from microbial sources harder than ever, since thousands of compounds have already been described in the literature. Singh and Barrett (2006) argue that the pharmaceutical industry should reinvest in natural product screening because nature is much bet-ter at designing antibiotics than humans. Despite these challenges, the new methods described here are likely to encourage the re-examination of natural product screen-ing as a source for novel antimicrobial agents. In this

section, we discuss the latest developments in the screen-ing techniques to enhance the biodiscovery potential.

High-throughput screening (HTS)Despite advances in synthetic medicinal chemistry the chemical diversity of such molecules is unparallel. Consequently, the success for generating new leads ultimately depends upon biological activity detection by screening against a target. Fortunately, now we are able to screen multiple samples against highly characterized targets unlike the largely cell-based systems of the past, where efforts were less tailored on the molecular aspects. Conversely, Goldman (2005) concluded that screening compounds using a cell-based biological approach could save three years and more than $300 million of the cost of developing a novel drug.

The traditional sources of chemical diversity, on which we have relied until now, might not be suitable for screen-ing against increasingly focused molecular targets. Thus, alternate strategies need to be explored. A complete gamut of new technology is available now, for screening novel natural products. Technology spanning from tradi-tional random screening based on whole-cell antimicro-bial activity that inhibits well-known validated targets, such as gyrases or penicillin binding proteins, to more complicated yet rational drug-designing approaches can be used.

A purely random screening approach is no longer con-sidered a practical route in drug discovery. In addition, to the now conventional 96-well micro titer methods, many new screening techniques are being aggressively developed (Broach and Thorner, 1996). One trend being observed nowadays in drug discovery programs has been towards a more rational approach to screening. Rather than using screens, which detect any antimicrobial activ-ity (open screening), researchers have recognized the value of using target-based screens.

High-throughput screening involves screening large libraries of small metabolites against a particular target. A successful HTS screening program should begin with a robust assay for the targets. In a study, Ausman (2001) has estimated that 100 000 results per system per day are likely to be dwarfed in the future because of the evolving capabilities of high-throughput screening. This technol-ogy is, simultaneously, cross-fertilized by advances in both automation and bioinformatics. He went ahead to compliment the ability of HTS describing it as truly awesome.

To detect, only the inhibitors of either a biosynthetic, metabolic, or a structural target, which is known or pre-dicted to be of some importance to the microorganisms, target-based screening can be used (Fleming et al., 1982). Conventional target-directed screening methods use a biochemical screen against a particular known target to assure a high degree of specificity and sensitivity for that target (Umezawa, 1982). Attractive chemical lead libraries for drug discovery programs can be provided by screening already known drugs on a given target and

Cri

tical

Rev

iew

s in

Bio

tech

nolo

gy D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y In

dian

Ins

titut

e of

Tec

hnol

ogy

New

Del

hi o

n 05

/18/

12Fo

r pe

rson

al u

se o

nly.

Page 22: Rare Actino

128 K. Tiwari and R. K. Gupta

Critical Reviews in Biotechnology

the selective chemical optimization of the observed “side activities” (Wermuth, 2004).

Since the early 1990s, research has strongly relied on high-throughput screening (HTS) for novel hit identifica-tion (Beggs and Long, 2002). Payne et al. (2007) and others suggest a reason for the failures of this approach, which has been the lack of chemical diversity in the chemi-cal libraries (Mochalkin et al., 2009; O’Shea and Moser, 2008). Unfortunately, a high-throughput screen of the potential targets, provided in abundance by the genomic revolution, has not been particularly successful.

Bioinformatic toolsAssay designing has completely been revolutionized today with the development of bioinformatics tools for interpreting and analyzing genomic as well as proteomic data. The molecular techniques used to manipulate and transform post genomic technologies, such as transcrip-tomics and proteomics, into drug targets has created a revolution in the field of natural product discovery (Walters and Namchuk, 2003).

With a recent confluence of powerful new drug discovery techniques: combinatorial chemistry, and sequence and functional genomic analysis the chance of discovering a novel bioactive agent by screening natu-ral products has increased considerably. It is because natural products are still unsurpassed in their ability to provide novelty and complexity. Recently, progress has been made in drug discovery from actinomycetes with high-throughput screening and fermentation, mining genomes for the cryptic pathways, and combinatorial biosynthesis to generate new secondary metabolites related to existing pharmacophores (Baltz, 2008; Bull and Stach, 2007). Metagenomic screening for DNA from environmental samples provides an alternative way to revive natural product screening (Handelsman, 2004; Schloss and Handelsman, 2005). A combination of these technologies can bring the untapped power back in the search for new antimicrobial agents.

Metabolite profilingA diverse group of microorganisms must be initially screened, to determine the best source of novel bioac-tive metabolites. Following pre-selection of the isolates according to taxa and metabolic profiles, they can be taken further for secondary screening. Based on their metabolic profiles (HPLC-DAD) the proportion of the novel to known metabolites can also be estimated. For this, the previously screened organisms and microbial colonies that have developed from identical environ-mental propagules (de-replication) on primary isolation plates needs to be recognized and excluded. By compar-ing the morphological characteristics of the isolated colo-nies, such as color, shape, consistency, dereplication can be easily accomplished (Bull et al., 1992; Donadio et al., 2002). This will enable the production of large ampli-con libraries of taxonomically unique organisms, which can greatly assist the selection of bioactive compounds

form large commercial screening operations. In studies describing chemical screening procedures (Holtzel et al., 1998), complex mixtures of metabolites after growth and fermentation are separated, purified, and identified using a high-pressure liquid chromatography with diode array detection (HPLC), diode array UV/visible spectra, and mass spectrometry (MS). In the past HPLC-DAD screening for metabolite profiling has been success-fully used (Bull and Stach, 2007; Fiedler et al., 2005). For further investigation of microbial metabolomes, metabolite-profiling techniques with greater resolving power are needed.

Genomics and proteomicsThe primary driving force for the increasing interest of pharmaceutical industry in microbial genomics is the belief in target-specific screening and identification of new targets. New means to identify novel agents within known chemical diversity can be provided by microbial genomics. Many novel potential target genes can now be identified, which can enable the synthesis of large quan-tities of target proteins for further screening purposes.

For the development of novel screens, additional strategies are being widely explored that can be applied to almost all the genes identified as pharmaceutically relevant. These strategies involve numerous whole-cell approaches to obtain target specificity using genetically altered strains (Bostian and Schmid, 1997; Tomoda and Omura, 1990). These whole-cell approaches overall rely on manipulation of the gene or of its expression, to gener-ate a characteristic phenotype. How successful they will be in achieving target specificity is yet to be determined. The application of gene expression micro arrays for these mechanism-of-action studies holds many promises. Though still untested, such micro arrays can provide us with a powerful new tool for characterizing screening hits and lead compounds in the future.

Presently, proteomics is also being actively applied in pharmaceutical research and development (Ashton, 1999; Cutler et al., 1999) particularly in the areas of drug discovery and target selection (e.g., via proteome differ-ence analysis of pathogenic versus nonpathogenic organ-isms, normal versus dysfunctional states, and disruption of stress-induced protein synthesis). Proteomics can also promote studies for the determination of the mode of action of a drug along with its toxicological screening and the monitoring of disease progression during clinical trials of the molecule.

Genome mining for cryptic antibiotic pathwaysMany unknown valuable metabolites might get over-looked while culturing microorganisms under stan-dardized laboratory conditions. It seems that over 90% of the genes or gene clusters responsible for secondary metabolite biosynthesis go unnoticed (Ishikawa, 2008). Genomics can be extremely helpful in the identifica-tion of cryptic (or orphan) biosynthetic gene clusters; particularly genome scanning provides an efficient way

Cri

tical

Rev

iew

s in

Bio

tech

nolo

gy D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y In

dian

Ins

titut

e of

Tec

hnol

ogy

New

Del

hi o

n 05

/18/

12Fo

r pe

rson

al u

se o

nly.

Page 23: Rare Actino

Rare actinomycetes: a potential storehouse for novel antibiotics 129

© 2012 Informa Healthcare USA, Inc.

to discover natural-product gene clusters. In a study, Zazopoulos et al. (2003) reported, through a genomics-guided approach, that most biosynthetic gene clusters in Streptomyces are cryptic. His study created a paradigm shift, which later initiated the field of genomic mining for discovering novel metabolites.

Though phenotypically silent, these gene clusters can be activated by either nonstandard fermentation or genetic manipulation, or both. According to a recent study many biosynthetic genes remain silent and such “cryptic”or “orphan” pathways are only activated under specific conditions (Ishikawa, 2008). Activation of these phenotypically silent genes or gene clusters could, more efficiently, enable the discovery of a large number of novel antibiotics. Based on this notion, he began a study, which he called ASAP (activation of silent antibiotics productivity). His approach refers to an idea for discovering novel antibiotics as soon as pos-sible instead of a particular technique. He further sug-gested numerous ways of activating them, for example, artificial control of the SARP-family transcriptional regulator genes (Ishikawa, 2008).

In another study Scherlach and Hertweck (2009) gave an overview on the strategies to trigger biosynthetic path-ways. They emphasized that biosynthetic gene clusters can be triggered to yield cryptic natural products through external cues, co-cultivation and genomic approaches such as genome mining, epigenetic remodeling, and engineered pathway activation. Such new approaches may free us from the arduous classical techniques such as culture condition improvement techniques and obtain-ing mutant strains.

Culture-based screeningDeveloping agents showing activity against more than a small set of pathogens is indeed a significant chal-lenge. Furthermore, isolates can also be screened for inhibition of growth of a panel of pathogens that include strains resistant to all of the antibiotics com-monly used against them. Plate assays can be used to screen a new isolate, which inhibits all of these strains to assess if it might be producing one or more novel compounds. The culture-based screening approaches still have a place in the search for new compounds they just need to be novel and specifically designed to exclude rediscovering already known compounds. Novel culture-dependent approaches when teamed with genomics can increase our understanding of the potential of microbial world.

Luminescence assaysIn the development of in-vivo drug screening assays, an innovative approach is BL whole-animal cellular and molecular imaging, which takes advantage of the advancements of the BL reporter gene and low-light imaging technologies (Contag, 2002). Recently, Roda et al. (2003) report the application of bioluminescence and chemiluminescence assays in drug screening, both

for in vitro and in vivo studies. He devoted particular attention to the latest and the most innovative biolumi-nescence and chemiluminescence-based technologies for screening drugs, like assays based on genetically modified cells, bioluminescence resonance energy transfer (BRET)-based assays, and in vivo imaging assays using transgenic animals or bioluminescent markers with its possible relevance in the future.

Other

Chemogenomics driven lead finding was reported by Klabunde (2007). The pool of compounds for screening is extended from known drugs to a set of bioactive mol-ecules, which have been rationally composed following the paradigm “similar receptors bind similar ligands” (Klabunde, 2006). Hill et al. (1998) recently reviewed the range of screens used in the search for biopharmaceutics and the success achieved with enzyme inhibition, recep-tor binding, and cell function assays. Hertzberg (1993) has strongly held his viewpoint that biopharmaceutics leads are more likely to be detected in cell function assays than in-vitro assays. Many new marine natural products have been successfully discovered by biological and chemical screening procedures.

Conclusion and perspectives

Microbial diversity is known to be an untapped resource of all kinds of which less than 1% is estimated to be represented in the strain collection’s the world over. Of special interest are the previously unexplored eco-logical niches or areas and regions in the world. These regions are regarded as bio-diversity hotspots, where it is believed that the effect of the local environment might result in the evolution of novel secondary metabolic pathways. If the search for organisms producing novel and useful bioactive molecules is to be successfully continued, those microorganisms that are under-repre-sented within compound collections show exceptional promise. The representatives of microbial groups with proven track records in the drug discovery process such as the actinomycetes are particularly interesting.

It is important that the quest for producing organisms should be expanded to include their new families, both cultured and un-cultured. Such optimism is largely based on the spectacular developments in the field of isolation and screening of actinomycetes that are now available, which has lead to the isolation of their novel species from diverse habitats. New prolific genera having the potential for producing neo-bioactive compounds have also been found. Further, with reasonable efforts, strains belonging to these unreported groups of actinomycetes are more likely to be isolated and cultured.

We conclude with full reflection that screening of rare actinomycetes will hopefully generate new leads in the near future. There have been a number of recent com-ments in this review about the need for using selective

Cri

tical

Rev

iew

s in

Bio

tech

nolo

gy D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y In

dian

Ins

titut

e of

Tec

hnol

ogy

New

Del

hi o

n 05

/18/

12Fo

r pe

rson

al u

se o

nly.

Page 24: Rare Actino

130 K. Tiwari and R. K. Gupta

Critical Reviews in Biotechnology

isolation and strain dereplication techniques. The review also highlights how novel-screening procedures can lead to the discovery of new bioactive compounds from rare actinomycetes isolated from geographically diverse samples. The discovery of novel bioactive metabolites from the unexplored microbial sources, though a chal-lenging endeavor, can bring substantial rewards if suc-cessful. However, with the advancement of scientific tools, it is just a matter of time, before the richness of these organisms stated as “storehouse of novel antibiot-ics” is appreciated. We wish to propose that it is time to reinvigorate the discovery of novel antibiotics from a proven source.

Website (http://www.namazu.org/)Website (http://www.nih.go.jp/saj/DigitalAtlas/)

Acknowledgments

We are very grateful to Prof. Hans-Peter Fiedler, Depart-ment of Microbiology/Biotechnology, University of Tübingen, Germany for his thorough revision of this review and providing us with his invaluable suggestions.

Declaration of interest

We acknowledge the financial support from MOEF and AICTE (8023/RID/NPROJ/RPS-38/2008-9).

ReferencesAmann RI, Ludwig W, Schleifer K-H. (1995). Phylogenetic

identification and in situ detection of individual microbial cells without cultivation. Microbiol Rev, 59, 143–169.

Ashton C. (1999). Reinventing drug development. Chem Ind, 11, 422–425.

Ausman DJ. (2001). Screening’s age of insecurity. Mod Drug Discovery, 4, 32–39.

Baltz RH. (2005). Antibiotic discovery from actinomycetes: will a renaissance follow the decline and fall? SIM News, 55, 186–196.

Baltz RH. (2006). Combinatorial biosynthesis of novel antibiotics and other secondary metabolites in actinomycetes. SIM News, 56, 148–160.

Baltz RH. (2007). Antimicrobials from actinomycetes: back to the future. Microbe, 2, 125–131.

Baltz RH. (2008). Renaissance in antibacterial discovery from actinomycetes. Curr Opin Pharmacol, 8, 557–563

Bardone MR, Paternoster M, Coronelli C. (1978). Teichomycins, new antibiotics from Actinoplanes teichomyceticus nov. sp. J Antibiot, 31, 170–177.

Beggs M, Long AC. (2002). High throughput genomics and drug discovery parallel universes or a continuum? Drug Discov World, 3, 75–80.

Bentley SD, Chater KF, Cerdeno-Tarraga AM, Challis GL, Thomson NR, James KD, Harris DE, Quail MA, Kieser H, Harper D, Bateman A, Brown S, Chandra G, Chen CW, Collins M, Cronin A, Fraser A, Goble A, Hidalgo J, Hornsby T, Howarth S, Huang CH, Kieser T, Larke L, Murphy L, Oliver K, O’Neil S, Rabbinowitsch E, Rajandream MA, Rutherford K, Rutter S, Seeger K, Saunders D, Sharp S, Squares R, Squares S, Taylor K, Warren T, Wietzorrek A, Woodwardm J, Barrell BG, Parkhill J, Hopwood DA. (2002). Complete genome sequence of the model actinomycetes Streptomyces coelicolor A3(2). Nature, 417, 141–147.

Blunt JW, Copp BR, Hu V-P, Munro HG, Northcote PT, Prinsep MR. (2007). Marine natural products. Nat Prod Rep, 24, 31–86.

Bostian KA, Schmid MB. (1997). New Antibacterial Targets and New Approaches for Drug Discovery. In: Busse WD, Zeiler HJ, Labischinski H, eds. Antibacterial Therapy: Achievements, Problems and Future Perspectives. Berlin: Springer-Verlag, 61–68.

Bredholt H, Fjaervik E, Johnsen G, Zotchev SB. (2008). Actinomycetes from sediments in the Trondheim Fjord, Norway: diversity and biological activity. Mar Drugs, 6, 12–24.

Broach JR, Thorner J. (1996). High-throughput screening for drug discovery. Nature, 384S, 14–16.

Bulina TI, Alferova IV, Terekhova LP. (1997). A new method for the isolation of actinomycetes with the use of microwave irradiation of soil samples. Mikrobiologiya, 66, 278–282.

Bulina TI, Terekhova LP, Tyurin MV. (1998). Use of electric pulses for isolation of actinomycetes from soil. Mikrobiologiya, 67, 556–560.

Bull AT, Stach JE. (2007). Marine actinobacteria: new opportunities for natural product search and discovery. Trends Microbiol, 15, 491–499.

Bull AT, Goodfellow M, Slater JH. (1992). Biodiversity as a source of innovation in biotechnology. Annu Rev Microbiol, 42, 219–257.

Bull AT, Stach JEM, Ward AC, Goodfellow M. (2005). Marine actinobacteria: perspectives, challenges, future directions. Antonie van Leeuwenhoek, 87, 259–276.

Butler MS, Buss AD. (2006). Natural products—the future scaffolds for novel antibiotics? Biochem Pharmacol, 71, 919–929.

Cai Y, Xue Q, Chen Z, Zhang R. (2009). Classification and salt-tolerance of actinomycetes in the Qinghai Lake water and Lakeside saline soil. J Sustainable Dev, 2, 107–110.

Cho SH, Hwang CW, Chung HK, Yang CS. (1994). A new medium for the selective isolation of soil actinomycetes. K J Appl Microbiol Biotechnol, 22, 561–563.

Ciabatti R, Cavalleri B. (1989). Ramoplanin (A/16686): a new glycodepsipeptide antibiotic from Actinoplanes. Progr Ind Microbiol, 27, 205–219.

Contag PR. (2002). Whole-animal cellular and molecular imaging to accelerate drug development. Drug Discov Today, 7, 555–562.

Cooper R, Das P, Federbush C, Mierzwa R, Patel M, Pramanik B, Truumees I. (1990). Characterization of peptidyl-nucleoside antifungal antibiotics from fermentation broth. J Ind Microbiol, 5, 1–8.

Cutler P, Birrell H, Haran M, Man W, Neville B, Rosier S, Skehel M, White I. (1999). Proteomics in pharmaceutical research and development. Biochem Soc Trans, 27, 555–559.

Davies J. (1999). Millennium bugs. Trends Biochem Sci, 24, M2–M5Demain AL. (2002). Prescription for an ailing pharmaceutical industry.

Nat Biotechnol, 20, 331–334.Donadio S, Monciardini P, Alduina R, Mazza P, Chiocchini C,

Cavaletti L, Sosio M, Puglia A-M. (2002). Microbial technologies for the discovery of novel bioactive metabolites. J Biotechnol, 99, 187–198.

Eccleston GP, Brooks PR, Kurtböke DI. (2008). The occurrence of bioactive micromonosporae in aquatic habitats of the Sunshine Coast in Australia. Mar Drugs, 6, 243–261.

Fenical W. (2006). Marine pharmaceuticals: past, present, and future. Oceanography, 19, 110–119.

Fenical W, Jensen PR. (2006). Developing a new resource for drug discovery: marine actinomycete bacteria. Nat Chem Biol, 2, 666–673.

Fiedler HP, Bruntner C, Bull AT, Ward AC, Goodfellow M, Potterat O, Puder C, Mihm G. (2005). Marine actinomycetes as a source of novel secondary metabolites. Antonie van Leeuwenhoek, 87, 37–42.

Fleming JD, Nisbet LJ, Brewer SJ. (1982). Target Directed Antimicrobial Screens. In: Bu’lock JD, et al., ed. Bioactive Microbial Products: Search and Discovery. New York: Academic Press, 107–130.

Galatenko OA, Terekhova LP, Preobrazhenskaya TP. (1990). The Application of Ultraviolet Irradiations to the Isolation of Rare Actinomycete Genera. In: Poisk Produtsentov Antibiotikov Sredi Aktinomitsetov Redkikh Rodov (Search for Antibiotic Producers Among Rare Actinomycete Genera). Golym: Alma-Ata, 29–35.

Cri

tical

Rev

iew

s in

Bio

tech

nolo

gy D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y In

dian

Ins

titut

e of

Tec

hnol

ogy

New

Del

hi o

n 05

/18/

12Fo

r pe

rson

al u

se o

nly.

Page 25: Rare Actino

Rare actinomycetes: a potential storehouse for novel antibiotics 131

© 2012 Informa Healthcare USA, Inc.

Goldman MA. (2005). Digital drug discovery. Genome Biology, 6, 348–350.

Goodfellow M. (1983). Ecology of actinomycetes. Annu Rev Microbiol, 37, 189–216.

Goodfellow M. (2010). Selective Isolation of Actinobacteria. In: Baltz RH, Davies J, Demain AL, eds. Manual of Industrial Microbiology and Biotechnology. Section 1: Isolation and Screening of Secondary Metabolites and Enzymes, Bull AT, Davies JE (section eds). Washington: ASM Press, 3, 13–27.

Goodfellow M, Fiedler, H-P. (2010). A guide to successful bioprospecting: informed by actinobacterial systematics. Antonie van Leeuwenhoek, 98, 119–142.

Hamaki T, Suzuki M, Fudou R, Jojima Y, Kajiura T, Tabuchi A, Sen K, Shibai H. (2005). Isolation of novel bacteria and actinomycetes using soil-extract agar medium. J Biosci Bioeng, 99, 485–492.

Handelsman J. (2004). Soils—the Metagenomics Approach. In: Bull AT, ed. Microbial Diversity and Bioprospecting. Washington: ASM Press, 109–119.

Hayakawa M. (2008). Studies on the isolation and distribution of rare actinomycetes in soil. Actinomycetologica, 22, 12–19.

Hayakawa M, Nonomura H. (1987a). Efficacy of artificial humic acid as a selective nutrient in HV agar used for the isolation of soil actinomycetes. J Ferment Technol, 65, 609–616.

Hayakawa M, Nonomura H. (1987b). Humic acid-vitamin agar, a new medium for the selective isolation of soil actinomycetes. J Ferment Technol, 65, 501–509.

Hayakawa M, Tamura T, Nonomura H. (1991). Selective isolation of Actinoplanes and Dactylosporangium from soil by using gamma-collidine as the chemoattractant. J Ferment Bioeng, 72, 426–432.

Hayakawa M, Kajiura T, Nonomura H. (1991a). New methods for the highly selective isolation of Streptosporangium and Dactylosporangium from soil. J Ferment Bioeng, 72, 327–333.

Hayakawa M, Sadakata T, Kajiura T, Nonomura H. (1991b). New methods for the highly selective isolation of Micromonospora and Microbispora from soil. J Ferment Bioeng, 72, 320–326.

Hayakawa M, Iino H, Takeuchi S, Yamazaki T. (1997). Application of a method incorporating treatment with Chloramine-T for the selective isolation of Streptosporangiaceae from soil. J Ferment Bioeng, 84, 599–602.

Hertzberg RP. (1993). Whole cell assays in screening for biologically active substances. Curr Opin Biotechnol, 4, 80–84.

Hill DC, Wrigley SK, Nisbet LJ. (1998). Novel screen methodologies for identification of new microbial metabolites with pharmacological activity. Adv Biochem Eng Biotechnol, 59, 75–121.

Holtzel A, Kemter C, Metzger JW, Jung G, Groth I, Fritz T, Fiedler H-P. (1998). Biosynthetic capacities of actinomycetes. 10. Spirofungin, a new antifungal antibiotic from Streptomyces violaceusniger TU 4113. J Antibiot, 51, 699–707.

Ishikawa J. (2008). Genome analysis system for actinomycetes: development and application. Actinomycetologica, 22(2), 46–49.

Iwai H, Takahashi Y. (1992). Selection of Microbial Sources of Bioactive Compounds. In: Omura S, ed. The Search for Bioactive Compounds from Microorganisms. New York: Springer-Verlag, 281–302.

Kim CJ, Lee KH, Shimazu A, Kwon OS, Park DJ. (1995). Isolation of rare actinomycetes in various types of soil. K J Appl Microbiol Biotechnol, 23, 36–42.

Kizuka M, Enokita R, Takahashi K, Okazaki T. (1997). Distribution of the actinomycetes in the Republic of South Africa investigated using a newly developed isolation method. Actinomycetologia, 11, 54–55.

Klabunde T. (2006). Chemogenomic approaches to ligand design. In: Rognan D, ed. Ligand design for G protein-coupled receptors. Weinheim: Wiley-VCH.

Klabunde T. (2007). Chemogenomic approaches to drug discovery: similar receptors bind similar ligands. Br J Pharmacol, 152, 5–7.

Lam KS. (2006). Discovery of novel metabolites from marine actinomycetes. Curr Opin Microbiol, 9, 245–251.

Lamari L, Zitouni A, Boudjella H, Badji B, Sabaou N, Lebrihi A, Lefebvre G, Seguin E, Tillequin F. (2002). New dithiolopyrrolone antibiotics from Saccharothrix sp. SA 233. I. Taxonomy, fermentation, isolation and biological activities. J Antibiot, 55, 696–701.

Lancini G, Lorenzetti R. (1993). Biotechnology of Antibiotics and other Bioactive Microbial Metabolites. New York, London: Plenum Press, 49–57.

Lazzarini A, Cavaletti L, Toppo G, Marinelli F. (2001). Rare genera of actinomycetes as potential producers of new antibiotics. Antonie van Leeuwenhoek, 79, 399–405.

Lechevalier HA, Lechevalier MP. (1967). Biology of actinomycetes. Annu Rev Microbiol, 21, 71–100.

Li-Hua H, Qi-Ren L, Cheng-Lin J. (1996). Diversity of soil actinomycetes in Japan and China. Appl Environ Microbiol, 62, 244–248.

Li Yu. V, Terekhova LP, Gapochka MG. (2002a). Isolation of actinomycetes from soil using extremely high-frequency radiation. Mikrobiologiya, 71, 119–122.

Li Yu. V, Terekhova LP, Alferova IV, Gapochka MG. (2002b). The use of EHF radiation in different wavelength bands for the selective isolation of actinomycetes from soil. Biomed Radioelektron, 5, 20–24.

Long PF, Wildman HG, Amphlett GE. (1994). The use of statistical models to predict the effects of pretreatments on the total viable counts of actinomycetes isolated from soil. Actinomycetes, 5, 1–8.

Miquely E, Martin C, Hardisson C, Manzanal MB. (1993). Synchronous germination of Streptomyces antibioticus spores: tool for the analysis of hyphal growth in liquid. FEMS Microbiol Lett, 109, 123–300.

Mochalkin I, Miller JR, Narasimhan L, Thanabal V, Erdman P, Cox PB, Prasad JV, Lightle S, Huband MD, Stover CK. (2009). Discovery of antibacterial biotin carboxylase inhibitors by virtual screening and fragment-based approaches. ACS Chem Biol, 4, 397–399.

Newman DJ, Cragg GM. (2007). Natural products as sources of new drugs over the last 25 years. J Nat Prod, 70, 461–477.

Nisbet LJ. (1982). Current strategies in the search for bioactive microbial metabolites. J Chem Technol Biotechnol, 32, 251–270.

Nolan RD, Cross T. (1988). Isolation and Screening of Actinomycetes. In: Goodfellow M, Williams ST, Mordarski M, eds. Actinomycetes in Biotechnology. London: Academic Press, 2–8.

Nonomura H. (1988). Isolation, taxonomy and ecology of soil actinomycetes. Actinomycetologia, 3, 45–54.

Okami B, Hotta AK. (1988). Search and Discovery of New Antibiotics. In: Goodfellow M, Williams ST, Mordarski M, ed. Actinomycetes in Biotechnology. Oxford: Pergamon Press, 33–67.

Okoro CK, Brown R, Jones AL, Andrews BA, Asenjo JA, Goodfellow M, Bull AT. (2009). Diversity of culturable actinomycetes in hyper-arid soils of the Atacama Desert, Chile. Antonie van Leeuwenhoek, 95, 121–133.

Omura S, Ikeda H, Ishikawa J, Hanamoto A, Takahashi C, Shinose M, Takahashi Y, Horikawa H, Nakazawa H, Osonoe T, Kikuchi H, Shiba T, Sakaki Y, Hattori M. (2001). Genome sequence of an industrial microorganism Streptomyces avermitilis: deducing the ability of producing secondary metabolites. Proc Natl Acad Sci USA, 98, 12215–12220.

O’Shea R, Moser HE. (2008). Physicochemical properties of antibacterial compounds: implications for drug discovery. J Med Chem, 51, 2871–8.

Palleroni NJ. (1980). A chemotactic method for the isolation of Actinoplanaceae. Arch Microbiol, 128, 53–55.

Payne DJ, Gwynn MN, Holmes DJ, Pompliano DL. (2007). Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat Rev Drug Discov, 6, 29–40.

Perić-Concha Natasa, Long PF. (2003). Mining the microbial metabolome: a new frontier for natural product lead discovery. Drug Discov Today, 8, 1078–1084.

Pfefferle C, Theobald U, Gürtler H, Fiedler H-P. (2000). Improved secondary metabolite production in the genus Streptosporangium by optimization of the fermentation conditions. J Biotechnol, 80, 135–142.

Roda A, Guardigli M, Pasini P, Mirasoli M. (2003). Bioluminescence and chemiluminescence in drug screening. Anal Bioanal Chem, 377, 826–833.

Sabaou N, Boudjella H, Bennadji A, Mostefaoui A, Zitouni A, Lamari L, Bennadji H. (1998). Les sols des oasis du Sahara algérien, source d’actinomycètes rares producteurs d’antibiotiques. Sécheresse, 9, 147–153.

Cri

tical

Rev

iew

s in

Bio

tech

nolo

gy D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y In

dian

Ins

titut

e of

Tec

hnol

ogy

New

Del

hi o

n 05

/18/

12Fo

r pe

rson

al u

se o

nly.

Page 26: Rare Actino

132 K. Tiwari and R. K. Gupta

Critical Reviews in Biotechnology

Scherlach K, Hertweck C. (2009). Triggering cryptic natural product biosynthesis in microorganisms. Org Biomol Chem, 7, 1753–1760.

Schloss PD, Handelsman J. (2005). Metagenomics for studying unculturable microorganisms: cutting the Gordian knot. Genome Biol, 6, 229–232.

Singh SB, Barrett JF. (2006). Empirical antibacterial drug discovery-foundation in natural products. Biochem Pharmacol, 71, 1006–15.

Sogin ML, Morrison HG, Huber JA, Welch DM, Huse SM, Neal PR, Arrieta JM, Herndl GJ. (2006). Microbial diversity in the deep sea and the underexplored “rare biosphere”. Proc Natl Acad Sci U S A, 103, 12115–12120.

Sosio M, Bossi E, Bianchi A, Donadio S. (2000). Multiple peptide synthetase gene clusters in actinomycetes. Mol Gen Genet, 264, 213–221.

Stach JEM, Bull AT. (2005). Estimating and comparing the diversity of marine actinobacteria. Antonie Van Leeuwenhoek, 87, 3–9.

Steffan RJ, Goskøyr J, Bej AK, Atlas RM. (1988). Recovery of DNA from soil and sediments. Appl Environ Microbiol, 54, 2908–2915.

Tishkov S. (2001). Bioactive Products from Actinomycetes–antibiotics, Enzyme Inhibitors, Immunomodulators. In: Moncheva P, Tishkov S, Chipeva V, ed. Innovative Aspects in Biotechnology of Prokaryotes. Sofia: National bank for industrial microorganisms and cell cultures, 111–138.

Tomoda H, Omura S. (1990). New strategy for discovery of enzyme inhibitors: screening with intact mammalian cells or intact microorganisms having special functions. J Antibiot, 43, 1207–l 223.

Umezawa H. (1982). Low molecular-weight enzyme inhibitors of microbial origin. Annu Rev Microbiol, 36, 75–99.

Walters WP, Namchuk M. (2003). Designing screens: how to make your hits a hit. Nat Rev Drug Discov, 2, 259–266.

Ward DM, Weller R, Bateson MM. (1990). 16S rRNA sequences reveal numerous uncultured microorganisms in a natural community. Nature, 345, 63–65.

Watve MG, Shejval V, Sonawane C, Rahalkar M, Matapurkar M, Shouche Y, Patole M, Phadnis N, Champhekar A, Damle K, Karandikar S, Kshirsagar V, Jog M. (2000). The ‘K’ selected oligophilic bacteria: a key to uncultured diversity? Curr Sci, 78, 1535–1542.

Watve G, Tickoo R, Jog MM, Bhole BD. (2001). How many antibiotics are produced by the genus Streptomyces? Arch Microbiol, 176, 391–392.

Weinbauer MG, Beckmann C, Hofle MG. (1998). Utility of green fluorescent nucleic acid dyes and aluminum oxide membrane filters for rapid epifluorescence enumeration of soil and sediment bacteria. Appl Environ Microbiol, 64, 5000–5003.

Wermuth CG. (2004). Selective optimization of side affinities: another way for drug discovery. J Med Chem, 47, 1303–1314.

Williams ST, Wellington EMH. (1982). Principles and problems of selective isolation of microbes. In: Bu’lock JD, Nisbet LJ, Winstanley DJ, ed. Bioactive microbial products: search and discovery. London: Academic Press, 9–26.

Zazopoulos E, Huang K, Staffa A, Liu W, Bachmann BO, Nonaka K, Ahlert J, Thorson JS, Shen B, Farnet CM. (2003). A genomics-guided approach for discovering and expressing cryptic metabolic pathways. Nat Biotechnol, 21, 187– 190.

Zengler K, Walcher M, Clark G, Haller I, Toledo G, Holland T, Mathur EJ, Woodnutt G, Short JM, Keller M. (2005). High-throughput cultivation of microorganisms using microcapsules. Methods Enzymol, 397, 124–130.

Zinder SH. (2002). The future for culturing environmental organisms: a golden era ahead? Environ Microbiol, 4, 14–15.

Zitouni A, Boudjella H, Mathieu F, Sabaou N, Lebrihi A. (2004a). Mutactimycin PR, a new anthracycline antibiotic from Saccharothrix sp. SA 103. I. Taxonomy, fermentation, isolation and biological activities. J Antibiot, 57, 367–372.

Zitouni A, Lamari L, Boudjella H, Badji B, Sabaou N, Gaouar A, Mathieu F, Lebrihi A, Labeda DP. (2004b). Saccharothrix algeriensis sp. nov., isolated from Saharan soil. Int J Syst Evol Microbiol, 54, 1377–1381.

Cri

tical

Rev

iew

s in

Bio

tech

nolo

gy D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y In

dian

Ins

titut

e of

Tec

hnol

ogy

New

Del

hi o

n 05

/18/

12Fo

r pe

rson

al u

se o

nly.