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Polish Journal of Microbiology2012, Vol. 61, No 2, 95104

MINIREVIEW

Introduction

e extensive use of antibiotics has led to growingresistance and the spread of many bacterial pathogens,which now constitutes a serious medical problem.For this reason, the number of studies aimed at devel-oping new analogs of known antibiotics, e.g. oxazoli-dinones, glycopeptides, quinolones, aminoglycosides,tetracyclines and ketolides (euretzbacher, 2011),and at identifying novel antibacterial therapeutics andstrategies, is growing exponentially. Positive valida-tion of new antimicrobial agents is oen connectedwith the discovery of novel targets. To illustrate thispoint, the so-called switch region of bacterial RNA

polymerase, that does not overlap the rifamycin bind-ing site, has been confirmed as the target of mycopyro-nin, corallopyronin, ripostatin and lipiarmycin anti-biotics which are not cross-resistant with rifamycins(Srivastava et al., 2011). It was also recently postu-lated that NF-B (nuclear transcription factor-B),which is crucial for the cellular response to stressand inammation caused by e.g. microbial infection,could represent a target for antimicrobial and antiviraltherapies (Vitiello et al., 2012). In addition, there is cur-rent controversy over whether fatty acid biosynthesispathways may constitute a novel promising target for

antibiotics to control bacterial pathogens, particu-

larlyStaphylococcus aureus (Parson and Rock, 2011).Potential antibacterial treatments include the use ofantimicrobial peptides, antivirulence strategies andtherapeutic antibodies (Fernebro, 2011), as well as plant-derived compounds, metal nanoparticles and bacterio-phage lytic enzymes.

Plant-derived compounds, metal nanoparticles andbacteriophage lysins, which are the subject of thisreview, may be considered new antimicrobials due totheir proven and substantial antibacterial eect, whichis, however, weaker than that of common antibioticsproduced by bacteria and fungi (Hemaiswarya et al.,2008). In the last decade, the first steps in elucidatingthe mechanisms of antibacterial activity and the cel-

lular targets of plant-derived compounds have beenmade, with phenolics, and especially avones, beingthe subject of the majority of studies. Flavones causedisruption of the bacterial cytoplasmic membrane andinhibit energy metabolism (Tsuchiya and Iinuma, 2000;Plaper et al., 2003). ese compounds can also attenu-ate the pathogenicity of various bacteria by their abilityto inhibit quorum-sensing signal receptors, sortase andurease activity, listeriolysin O, coagulase and -toxinsecretion, and by neutralizing bacterial toxins (forreview see Cushnie and Lamb, 2011). ere have alsobeen a considerable number of reports describing the

antibacterial eect of another group of plant-derived

Synergy Between Novel Antimicrobialsand Conventional Antibiotics or Bacteriocins

KRYSTYNA I. WOLSKA*, KATARZYNA GRZE and ANNA KUREK

Department of Bacterial Genetics, Institute of Microbiology, Faculty of Biology,University of Warsaw, Warsaw, Poland

Received 9 November 2011, revised 7 April 2012, accepted 7 May 2012

A b s t r a c t

Due to the alarming spread of resistance to classic antimicrobial agents, innovative therapeutic methods to combat antibiotic-resistantbacterial pathogens are urgently required. is minireview examines the enhancement of antibiotic efficacy by their combination withnew antimicrobials, such as plant-derived compounds, metal ions and nanoparticles and bacteriophage lytic enzymes. e mechanisms ofthe observed synergy are also described. e promising results of basic research indicate that in future, combined therapy may be appliedin human and veterinary medicine, agriculture and the food industry to combat bacterial pathogens.

K e y w o r d s: antibiotics, bacteriophages, nanoparticles, plant compounds, synergy

* Corresponding author: K.I. Wolska, Department of Bacterial Genetics, Institute of Microbiology, University of Warsaw, Mieczni-kowa 1, 02-096 Warsaw, Poland; phone: (+48) 22 55 41 402; fax: (+48) 22 55 41 402; e-mail: [email protected]


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K.I. Wolska et al. 296

compounds, the terpenes, but only a few discuss themolecular basis of their antibacterial activity (for reviewsee Kureket al., 2011; Wolska et al., 2010). For example,pentacyclic triterpenoids can inhibit insoluble glycansynthesis byStreptococcus mutans (Kozai et al., 1999)and peptidoglycan metabolism in Listeria monocyto-

genes (Kureket al., 2010), and also inuence Escherichiacoli gene expression and biofilm formation (Ren et al.,2005; Grudniak et al., 2011). It was also shown thatditerpenoids have potent anti-biofilm activity againststaphylococci (Walencka et al., 2007). In addition, thesesquiterpene farnesol was found to inhibit S. aureusgrowth by aecting the mevalonate pathway of isopren-oid synthesis (Kaneko et al., 2011).

Metal ions and nanoparticles, especially silver com-pounds, constitute another group of potent antimicro-

bials that have already been applied in medicine andpharmacology (Chopra, 2007; Li et al., 2006; Monteiroet al., 2009). ey are used as antibacterial surface coat-ings on medical devices, such as venous and urinarycatheters, implants and megaprostheses (Hamill et al.,2007; Hardes et al., 2010). Silver nanoparticles (AgNPs)display remarkable antimicrobial activity against Pseu-domonas aeruginosa, E. coli and Enterobacter cloacae,being more active against Gram-negative than againstGram-positive bacteria (Im et al., 2011). Metal ionsand nanoparticles are safer in vitro and have a greaterantibacterial eect when stabilized by various polymer

surfactants (Lin et al., 2012). Silver nanoparticles candisrupt bacterial membranes (Singh et al., 2008), causemembrane lipid peroxidation (Neal, 2008), alter geneexpression (Loket al., 2006), and when inside the cell,they may also damage DNA and impair the respiratorychain and cell division (Rai et al., 2009).

e lytic enzymes of bacteriophages may also beconsidered as novel antimicrobials. Bacteriophage the-rapy to treat bacterial infections has been well studied,but the extensive literature on this subject will not beconsidered here (for review see Chibani-Chennoufiet al., 2004; Grski et al., 2009). An alternative to wholephage particles is the application of phage lysins:enzymes that are active against Gram-positive bacte-ria. It was shown that the lytic enzyme PhyPH is activeagainst Bacillus anthracis strains (Yoong et al., 2006),and the S. aureus bacteriophage MR11 lysin, desig-nated MV-L, can inhibit a number ofS. aureus strains,including those that are methicillin-resistant (MRSA)or vancomycin-intermediate (VISA) (Rashel et al.,2007). Using a mouse model, Grandgigard and cowork-ers (2008) demonstrated that the recombinant phagelysine Clp-1 may be useful in therapy for pneumococcal

meningitis, and Nelson et al. (2001) found that the lysinisolated from a virulent C

1phage, specific for group C

streptococci, can prevent and eliminate upper respira-tory tract colonization by group A streptococci.

e compounds listed above display antibacterialactivity when used alone, but there is also the possi-bility of using them in combination with conventionalantibiotics in order to improve their efficacy. Com-bination therapy, i.e. the simultaneous treatment ofinfections with more than one drug, may constitutean efficient strategy to combat antibacterial resistance.is minireview summarizes current data on the syner-gistic activity of antibiotics in combination with plant-derived compounds, metal ions and nanoparticles, andbacteriophage lytic enzymes. e examples of synergybetween novel antimicrobials and antibiotics / bacterio-cins are also listed in Table I. e determination of syn-ergy between two compounds is based on calculationof the FICI (fractional inhibitory concentration index),where a value of 0.5 indicates a synergistic interaction

(EUCAST, 2000). e possible mechanisms underlyingthese interactions are described in a separate chapter.

Synergy between plant-derived compoundsand antibiotics or bacteriocins

ere have been a substantial number of reportson synergistic antibacterial activity between variouspurified plant-derived compounds and plant oils, andantibiotics (mainly -lactams) against Staphylococcusaureus including (MRSA). e most relevant findings

from these studies will be presented in chronologicalorder. Brehm-Stecher and Johnson (2003) observedthat treatment with low concentrations of the sesqui-terpenoids nerolidol, bisabolol and apritone enhancedbacterial susceptibility to ciprooxacin, clindamycin,erythromycin, gentamicin, tetracycline and vancomy-cin. Synergism was demonstrated between ampicillinand ethanolic extracts from 10 Indian medicinal plants,including Camelia sinensis (Chinese tea), that are richin alkaloids, glycosides, avanoids, phenols and sapo-nins (Aqil et al., 2005), and quinic acid gallates fromCaesalpina spinosa could intensify the susceptibility ofMRSA to oxacillin (Kondo et al., 2006). Grande et al.(2007) found that the antimicrobial activity of bac-teriocin produced byEnterococcus faecalis, enterocinAS-48, against S. aureus was potentiated when appliedin combination with phenolic compounds such as car-

vacrol. Synergy was demonstrated between the diter-penoids salvipisone and aethiopinone, and antibioticsfrom the -lactam, glycopeptide and oxazolidinonegroups (Walencka et al., 2007). Nascimento et al. (2007)observed synergistic activity between ampicillin andthe Brazilian plant Eremanthus erythropappus oil and

-bisakolene. e hop (Humulus lupulus)-derived com-pounds, lupulone and xanthohumol, showed synergywith tobramycin and ciprooxacin (Natarajan et al.,2008). A synergistic eect of kaempferol glycosides


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Antibiotics and novel antimicrobials2 97

purified from Laurus nobilis and uorochinolones onMRSA was shown by Liu et al. (2009), while the efficacyof galangin, a avanol isolated from Alpinia officina-rum, administered with ceazidime, against penicillin-resistant S. aureus (PRSA) was demonstrated by Eum-keb and coworkers (2010). In a study of the synergisticantimicrobial activity of pentacyclic triterpenoids (e.g.betulinic acid) combined with methicillin or vancomy-cin, it was found that various combinations of thesecompounds could reduce their minimal inhibitory con-centrations (MICs) by 0.0550% (Chung et al., 2011).Two other pentacyclic triterpenoids, oleanolic acid andursolic acid, have recently been shown to act synergis-tically with ampicillin and oxacillin against S. aureusand Staphylococcusepidermidis grown in solution or asbiofilms (Kureket al., 2012).

In the last decade, there have been an appreciablenumber of reports describing synergy between plantcompounds and antibiotics against bacteria outsidethe genus Staphylococcus. e antibacterial eect ofnisin Z against Listeria monocytogenes ATCC 7644

and Bacillus subtilis ATCC 33712 was found to begreatly enhanced by a subinhibitory concentrationof thymol (Ettayebi et al., 2000), and the diterpenoidcarnosol reduced the MICs of various aminoglyco-

sides against vancomycin-resistant enterococci VRE(Horiuchi et al., 2007). Garo et al. (2007) showed thattreatment with asiatic acid and corosolic acid enhancedthe susceptibility ofPseudomonasaeruginosa bioilmsto tobramycin. Alcoholic extracts from 15 traditio-nal Indian medicinal plants exhibited synergy withtetracycline and ciprooxacin to inhibit the growthof ESbetaL (extended spectrum beta-lactamase)-pro-ducing E. coli and Shigella (Ahmad and Aqil, 2007).e combination of kaempferol with clindamycin orquercetin produced a large synergistic eect againstantibiotic-resistant Propionibacterium acnes (Lim et al.,2007). Studies by a Chinese group have confirmed thesynergistic activity between a herbal medicine iso-lated from Ramulus cinnamoni and tetracycline, gen-tamicin and streptomycin against nosocomical anti-biotic-resistant strains ofP. aeruginosa (Liu et al., 2007).Using transmission electron microscopy, Sivaroobanet al. (2008) observed cell damage in L. monocytogenescaused by a combination of nisin with either a grapeseed or a green tea extract rich in phenolic consti-

tuents. Combination with gerianol isolated from Heli-chrysum italicum, a member of the sunower family,significantly increased the efficacy of -lactams, quino-lones and chloramphenicol towards multidrug resistant

Plant compound

ymol Nisin L. monocytogenes Ettayebi et al., 2000EGCg Ampicillin + sulbactam MRSA Hu et al., 2001

EGCg Penicillin S. aureus Zhao et al., 2002

Baicalein E-lactams, tetracycline MRSA Fujita et al., 2005

7-methyljuglone Isoniazid M. tuberculosis Bapela et al., 2006

Carnosol Aminoglycosides VRE Horiuchi et al., 2007

Asiatic acid, corosolic acid Tobramycin P. aeruginosa Garo et al., 2007

Ellagic acid, tannic acid Novobiocin A. baumanii Chusri et al., 2009

Kaempferol glycosides Fluorochinolones MRSA Liu et al., 2009

Galangin Cefazidime PRSA Eumkeb et al., 2010

Oleanolic acid Rifampicin M. tuberculosis Ge et al., 2010

Betulic acid Methicillin, vancomycin S. aureus Chung et al., 2011Oleanolic acid, ursolic acid Ampicillin, oxacillin S. aureus, S. epidermidis Kureket al., 2012

Ag+ and AgNPs

Ag+ Vancomycin, amoxicillin, penicillin G S. aureus Shahverdi et al., 2007

AgNPs Polymyxin B Gram bacteria Ruden et al., 2009

AgNPs Ampicillin Gram+ bacteria Fayaz et al., 2010

Bacteriophages lytic enzymes

Cpl -1 Cefotaxime, moxioxacin S. pneumoniae Rogrguez-Cerrato et al., 2007

LysK Lysostaphin MRSA Becker et al., 2008

ClyS Oxacillin, vancomycin MRSA Daniel et al., 2010

LysH5 Nizin S. aureus Garcia et al., 2010

Table IExamples of synergy between novel antimicrobials and antibiotics/bacteriocins

Novel antimicrobial Antibiotic/bacteriocin Bacterial species Reference


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Enterobacter aerogenes, E. coli, P. aeruginosa and Aci-netobacter baumanii (Lorenzi et al., 2009). e antibac-terial activity of novobiocin was shown to be enhancedby the plant phenolics ellagic and tannic acids, whichincreased its eectiveness against multi-drug resistant

A. baumanii (Chusri et al., 2009). A crude leaf extractofHelichrysum pedunculatum enhanced the activity ofeight antibiotics from various groups against bacteriaimplicated in wound infections (Aiyegoro et al., 2010).Mulyaningsih et al. (2010) elucidated the synergisticproperties of two terpenoids from the essential oilof Eucalyptus globulus, aromadendrene and 1,8-cin-eole, against VRE. A notable study by Ge et al. (2010)described synergistic in vitro interactions between olea-nolic acid and isoniazid, rifampicin or ethambutanolagainstMycobacterium tuberculosis. e potent syner-

gism of ciprooxacin with extracts of medicinal plants,e.g.Angelica sinensis and Melissa officinalis, againstEnterobacteriaceae and P. aeruginosa has also recentlybeen reported (Garveyet al., 2011).

Synergistic activity between metal ionsor nanoparticles and antibiotics or bacteriocins

e majority of reports on the interaction betweenantibiotics and various forms of metals describe theeects of silver ions and silver nanoparticles (AgNPs).

In an early study, Modak and Fox (1985) identified syn-ergism between silver sulfadazine and piperacillin (anextended-spectrum penicillin antibiotic), both in vitroand in vivo. e antimicrobial activities of various anti-biotics in the presence of Ag+ ions have since been stud-ied more systematically and the greatest enhancing eectwas observed for vancomycin, amoxicillin and penicillinG against S. aureus rather than E. coli (Shahverdi et al.,2007). In contrast, the synergistic activity between sil-

ver nanoparticles (AgNPs) and ampicillin, gentamicin,kanamycin, streptomycin and vancomycin was subse-quently shown to be greater against E. coli and P. aeru-

ginosa than against S. aureus (Birla et al., 2009). It wasalso confirmed that silver nanoparticles can enhancethe antibacterial activity of chloramphenicol, being anactive carrier of this antibiotic (Patil et al., 2009). It hasyet to be determined whether nanoparticles pre-boundto an antibiotic produce a greater antimicrobial eectthansimultaneous addition of silver and the antibiotic(Durn et al., 2010). A number of studies have shownthat silver can act synergistically with compoundsother than antibiotics. e activity of AgNPs against anE. coli biofilm was increased by the lipopeptide biosur-

factant V9T14 (Rivardo et al., 2010), and synergy withchitosan against S. aureus has also been reported (Potaraet al., 2011). Ammons et al. (2011) recently showed thata silver wound dressing combined with the immune

molecule lactoferrin and the rare sugar-alcohol xylitol,reduced biofilm viability more eectively than standardsilver hydrogel.

So far there have been no reports of the direct syn-ergistic activity of gold nanoparticles (AuNPs) andantibiotics. Gu et al. (2003) found that AuNP-vanco-mycin conjugates can act as a potent inhibitor of VREand E. coli. It has also been demonstrated that AuNPsfunction as useful carriers for ciprooxacin and otheruoroquinolones (Tom et al., 2004). In the case ofE. coli, the AuNP conjugate showed greater antibacte-rial activity than free ciprooxacin (Rosemary et al.,2006). However, Burygin et al. (2009) found no dier-ence between the antibacterial activity of a gentamicinconjugate with AuNPs and the free antibiotic. A singlereport has described the synergistic interaction between

copper and an antibiotic erythromycin (Sultana et al.,2005). Synergism was observed between this antibioticand several other trace elements besides copper (e.g.cobalt, nickel, chromium), against both Gram-negativeand Gram-positive bacteria. Synergistic antimicrobialeects between metal ions and compounds other thanantibiotics have also been reported, the most well docu-mented of which is enhancement of the antimicrobialactivity of pomegranate extracts against clinical isolatesof S. aureus and P. aeruginosa by combination withcupric sulfate (Gould et al., 2009 a, b).

Antibiotics or bacteriocinsand bacteriophage lytic enzymes

ere have been several recent reports describ-ing interactions between bacteriophage-encoded lyticenzymes and classic antibiotics or bacteriocins. A syn-ergistic eect with penicillin and gentamicin wasobserved for lytic enzyme Cpl-1 encoded byStreptococ-cus pneumoniae lytic phage Cp-1 and also for anotherendolysin, Pal, encoded byS. pneumoniae lytic phageDp-1 (Lpez and Garca, 2004), against several pen-icillin-resistant and -sensitive S. pneumoniae strains(Loeer and Fischetti, 2003; Djurkovic et al., 2005).In vitro interactions between Cpl-1 and Pal with cefo-taxime and moxioxacin against antibiotic-susceptibleand antibiotic-resistant S. pneumoniae have also beenstudied. Synergistic activity was confirmed for thecombination of Cpl-1 and cefotaxime or moxioxacinand the eect was strain-dependent. It is noteworthythat greater synergy was observed for the combina-tion of these antibiotics with LytA, which is the majorpneumococcal autolysin (Rodrguez-Cerrato et al.,

2007). e combined eect of nisin and two S. aureuslytic phages, 35 and 88, was assessed, and a syner-gistic eect was observed in short-term experiments.However nisin adaptation and reciprocal resistance to


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both phages have prevented the practical application ofthis combined therapy (Martnez et al., 2008). Anothertwo endolysins, LysK, produced by staphylococcalbacteriophage K (OFlahertyet al., 2005) and the anti-staphylococcal bacteriocin, lysostaphin, synthesized byStaphylococcus simulans (Dajcs et al., 2000), exhibitedsynergy in killing MRSA (Becker et al., 2008). Recently,a novel chimeric lysin, ClyS, was engineered by fus-ing the N-terminal catalytic domain ofS. aureus Twortphage lysin with the C-terminal cell-wall targetingdomain of the phage NM3 lysin. e chimeric pro-tein displayed synergistic interactions with both van-comycin and oxacillin in vitro and its combination withoxacillin could prevent septic death in MRSA-infectedmice (Daniel et al., 2010).

Molecular basis of synergistic activities

ree categories of combination therapy can bedistinguished (Fischbach, 2011). e most commonstrategy utilizes the combination of drugs which inhibitdierent pathways within bacterial cells. An example ofsuch a strategy is treatment ofMycobacterium tubercu-losis infections with four drugs: 1) isoniazid, an inhibi-tor of fatty acid synthesis, 2) rifampicin, an inhibitorof RNA polymerase, 3) ethambutanol, an inhibitor ofarabinose transferases involved in cell wall biosynthesis,

and 4) pyrozinamide, with an as yet unknown mecha-nism of action (Ginsberg and Spigelman, 2007). esecond strategy is based on the inhibition of dierenttargets in the same pathway. e inhibition of folicacid synthesis by a combination of sulfamethoxazole,an inhibitor of dihydropteroate synthetase, and trime-thoprim, inhibiting dihydrofolate reductase, is based onthis strategy (Wormster et al., 1982). e third strategyrequires inhibition of the same target in dierent ways,e.g. the application of streptogramin and virginamycin,which both inhibit the peptidyl transferase center onthe 50S ribosomal subunit (Tu et al., 2005). It should benoted that such a combined antimicrobial eect is uti-lized in nature by antibiotic producers to compete eec-tively with other species (Ohnishi et al., 2008). Insteadof two antibiotics, combination therapy can utilizeantibiotics with their sensitizers: molecules that makethe co-applied antibiotic more eective by inhibitingenzymes responsible for antibiotic resistance or thosethat metabolize the drug. For example, diazabicyclooc-tanes (DBOs) are novel class A and class C -lactamaseinhibitors that are more potent than current commer-cially available inhibitors (Coleman, 2011). Similarly,

the synergistic antibacterial activity between variousplant-derived compounds increases the eectiveness ofherbal extracts in comparison with the isolated singleconstituents. In phytotherapy, this synergy is more dif-

ficult to dissect because plant extracts contain manyminor agents that may inuence the combined eect. Inspite of this, many synergistic activities between phyto-pharmaceuticals have been demonstrated, and in somecases the mechanism of this eect has been elucidated(Wagner and Ulrich-Merzenich, 2009).

e synergistic antimicrobial eect of an antibioticcombined with another agent requires interaction of thelatter compound with the bacterial resistance mecha-nism. e first details of the molecular basis of synergis-tic interaction between some plant-derived compoundsand various classes of antibiotics have recently beenrevealed. e ability of novel therapeutics to inhibitlactam- or ester-cleaving enzymes can result in synergywith -lactams. EGCg (epigallocatechin gallate) inhib-its penicillinase activity, thus restoring the eectiveness

of penicillin against S. aureus (Zhao et al., 2002) andpotentiating the eect of ampicillin and sulbactamagainst MRSA (Hu et al., 2001). e synergy betweengalangin and methicillin, ampicillin, amoxicillin, cloxa-cillin, penicillin G and cefazidime against S. aureus wasfound to be based on the marked inhibitory activity ofgalangin against penicillinase and -lactamase (Eumkebet al., 2010). e two antimicrobials in a combinationmay aect the same cellular target. For example, EGCgadministered with a -lactam antibiotic could inhibitpeptidoglycan synthesis (Yam et al., 1998; Zhao et al.,2001). Subsequently, Fujita et al. (2005) demonstrated

that the avone baicalein exhibits remarkable synergywith -lactam antibiotics against MRSA, possibly byinhibiting the activity of PBP 2a or by aecting pepti-doglycan structure, and Kuroda et al. (2007) demon-strated that the sesquiterpene farnesol inhibits recyclingof the C

55carrier of the murein monomer precursor,

thus contributing to increased bacterial susceptibility to-lactams. Several plant compounds appear to inhibitdefined targets in the bacterial cell. e avanol myric-etin was found to suppress DnaB helicase activity andglycosylated avones could inhibit topoisomerase IV,so these compounds have the potential to act synergis-tically with particular antibiotics (Hemaiswarya et al.,2008). Another mechanism of synergy is by increasingthe intracellular antibiotic concentration, which may beachieved by overcoming cellular barriers that preventantibiotics from penetrating the cell or by blocking bac-terial eux pumps that extrude such agents from thecell. e majority of reports have described the eect ofplant compounds on bacterial eux pumps. e indolealkaloid reserpine, a modulator of multidrug pumpsenhanced tetracycline activity against MRSA contain-ing the tetKdeterminant (Gibbons and Udo, 2000), and

baicalein inhibited TetK-dependent eux of tetracy-cline (Fujita et al., 2005). Certain plant-derived com-pounds, e.g. EGCg, have been shown to act as bacterialeux pump inhibitors (EPIs) and are able to restore


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the antibacterial eect of ineective antibiotics such asciprooxacin, preferentially against Gram-positive, butalso against Gram-negative species (Stavri et al., 2007).N-caeoylphenalkylamide derivatives were found to actas EPIs in S. aureus, especially in strains overexpressingthe multidrug eux transporter NorA (Michalet et al.,2007). Chusri et al. (2009) suggested that ellagic andtannic acids act as eux pump inhibitors inA. bauma-nii. It was recently demonstrated that the aforemen-tioned synergism between medicinal plant extractsand ciprooxacin is the result of inhibition of the euxpump in Gram-negative bacteria (Garveyet al., 2011).Another recent study showed that caeoylquinic acidsfromArtemisia absinthium preferentially bind to MajorFacilitator Super Family eux systems, which are keymultidrug resistance determinants in Gram-positive

bacteria (Fiamegos et al., 2011). Plant-derived com-pounds may also be involved in the transformationof a non-active antimicrobial into its active form. enaphthoquinone 7-methyljuglone was able to potenti-ate the eect of antituberculous drugs against extra-cellular and intracellular Mycobacterium tuberculosis,possibly due to the elevated synthesis of superoxide,which catalyzes the transformation of isoniazid into itsactive form (Bapela et al., 2006). A recent attempt toelucidate the mechanism of synergy between oleanolicand ursolic acids and ampicillin failed to produce anunequivocal answer. However, the inactivation of ampi-

cillin target, the PBPs (penicillin binding proteins), theinhibition of -lactamase translocation and increased-lactam transport mediated by these compounds, wereall excluded (Kureket al., 2012).

ere have been few studies on the molecular basisof synergy between antibiotics and metal nanoparticlesor bacteriophage lytic enzymes. It has been claimed thatthe synergism between nanoparticles and antibiotics orbacteriocins is based on the ability of the latter to helpnanoparticles reach their cellular targets. Synergisticactivity between silver nanoparticles and membrane-permeabilizing antimicrobial peptides, such as the lipo-peptide polymyxin B has been reported (Ruden et al.,2009). Polymyxin B is a cyclic polycationic lipopeptidethat disrupts the outer membranes of Gram-negativebacteria by interacting with lipid A (Schindler andOsborn, 1979), and it was postulated that such anti-microbial peptides allow nanoparticles to gain accessto their internal target site. Fayaz et al. (2010) showedthat AgNPs can act synergistically with several antibiot-ics, preferentially against Gram-negative bacteria, andthe greatest eect was observed with ampicillin. eseauthors proposed a model in which AgNPs associate

with ampicillin, these complexes interact with the bac-terial cell wall and subsequently inhibit the formationof peptidoglycan cross-links, leading to cell wall lysis.In addition, the AgNPs may prevent DNA unwinding

when inside the cell. It has also been established thatAuNPs are a very useful tool for drug delivery and serveas a stable and non-toxic platform for pharmaceuti-cals, enhancing their stability and improving targeting(Pissuwan et al., 2010).

e aforementioned synergy between two peptido-glycan hydrolases, endolysin LysK and lysostaphin, maybe due to the fact that LysK has two lytic domain (endo-peptidase and amidase) and thus is able to enhancethe lytic potential of lysostaphin, which has singlelytic domain (Becker et al., 2008). Garca et al. (2010)reported synergy between phage endolysin LysH5,which is active against a wide range of staphylococci(Obeso etal. 2008), and nisin in killing S.aureus inpasteurized milk. e MICs of nisin and LysH5 werediminished by 64- and 16-fold, respectively. It was

postulated that LysH5 activity might be increased bythe permeabilization of the cytoplasmic membrane bynisin, as was previously documented for the endolysinLys44 (Nascimento etal., 2008).

Conclusion

e number and variety of novel antimicrobialswhich show synergy with classic antibiotics and bac-teriocins is substantial. Many of these compoundshave already been used as an alternative to conven-

tional treatments in medicine and agriculture. How-ever, their widespread application is restricted, mainlybecause their mechanisms of action have not been fullycharacterized and their eect on eukaryotes has yetto be established. e problem of antibiotic resistanceamong bacteria has received much coverage in theliterature (Fernebro, 2011; Defoirdt etal., 2011). eproven synergistic activities of novel antimicrobialswith well known antibiotics provides some hope thatthe latter may still be of use to treat diseases caused byantibiotic-resistant bacteria. Due to their narrow actionspectrum and toxicity, bacteriocins were replaced byantibiotics in clinical use and are now extensively usedin food preservation (Riley and Wertz, 2002; Falagasand Kasiakou, 2005). Bacteriocin-resistance may becountered by the use of these compounds in combina-tion with novel antimicrobials. Such a strategy mightrestore the potential of bacteriocin (e.g. nisin) to elim-inate pathogenic bacteria, like S.aureus, from food.Currently, novel antimicrobials cannot replace antibiot-ics, but they may become valuable antibiotic comple-ments. In order to exploit these new antimicrobialseectively in synergistic combination therapy, it will

be necessary to determine the optimal ratio and dosingregimen, and to fully characterize the mechanisms oftheir activities by employing genomic, proteomic andmetabolomic technologies.


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Acknowledgment

is work was supported by Polish Ministry of Science andHigher Education grant NN 302 027937.

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