chemotherapeutic agents, chapter 38-43 · penilloaldehyde + sh h2n ooh penicillamin n s h o n h r o...
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Chemotherapeutic Agents, chapter 38-43
•Antibacterial compounds (procaryotes)•Antifungal compounds (eucarytotes)•Antiparasitic agents (eucarytotes) •Antiviral compounds
•Anticancer compounds
Different living organisms
Virus
Procaryotes
Eucaryotes
Bakteriea: Monocellular, no nucleus - DNA single strand, cell wall, asex. replic.
Mono or polycellularCell nucleus; DNAMay have cell wallsexual and / or asexual replication
Animals
Plants
Fungi
Protocista: - Protozoea - Algea
RNA or DNA + protein coating (not really a cell)Use other oramisms ribosomes for protein synth
Antibacterial compounds, chapter 38(- antimycobacterials)
•Synthetic antibacterials (chemotherapeutica)•Antibiotics
Antibiotics
Product from metabolism (natural product)(also applies if compd is prepared synthetically, or is a synthetic analog of a naturally occuring antibiotic/ semisynthetic compd)
Inhibit growth (bacteriostatic) or kill (bacteriocide) microorg.
Effective in low conc.
Antimicrobial chemotherapeutics: Antimicrobial comp ≠ Antibiotics
Grampositive bakterier:F. eks.Streptococcus Staphylococcus Bacillus - causes anthrax and gastroenteritis Clostridium - causes botulism, tetanus, gas gangrene, and pseudomembranous colitis Corynebacterium - causes diphtheria Listeria - causes meningitis
The cell walls of gram-positive bacteria are made up of twenty times as much murein or peptidoglycan than gram-negative bacteria. These complex polymers of sugars and amino acids cross-link and layer the cell wall. The thick outer matrix of peptidoglycan, teichoic acid, polysaccharides, and other proteins serve a number of purposes, including membrane transport regulation, cell expansion, and shape formation
Gram-negative bacteria have a unique outer membrane, a thinner layer of peptidoglycan, and a periplasmic spacebetween the cell wall and the membrane. In the outer membrane, gram-negative bacteria have lipopolysaccharides (LPS), porin channels, and murein lipoprotein all of which gram-positive bacteria lack. The gram-negative outer membrane which contains LPS, an endotoxin, blocks antibiotics, dyes, and detergents protecting the sensitive inner membrane and cell wall.
Gramnegative bakterier:F. eks.Spirochetes - causes syphilis, lyme disease Neisseria- causes meningococcus, gonorrhea
G+ and G- bacteria
Synthetic antibacterials (chemotherapeutica)
Antibacterial sulfonamides
Azo dyes Bayer etcLate 1800-century, ex.
NN N
HO3S
Metylorange
NN
O2N
Pararødt
HO
Salvarsan1. antisyphilis drug 1912
AsAs
HOOH
NH2
H2N
Screening of dyes as antibacterials
NN NH2
SO
OH2N
H2N
1932: Prontocil active against Streptoccocces infectionno activity on bacterial cultures
1935: Prontocil metabilized (azoreductase) to Sulfanilamid in vivo
NH2SO
OH2N (rel. toxisk)
Modern sulfa drugsr
NH2SO
OHNR
R: Aryl or hetroaryl
As As
As
Ar Ar
Ar
AsAs As
AsAsAr
ArAr
Ar Ar
Nøytral sulfonilamid dårlig vannløselig. Urine pH ca 6: Crystallization neutral form, kidney damageModern sulfa drugs pKa 5 – 7; better solubility
ArSO
OHN
Sulfametoksasol pKa 6.1
ArSO
ON
- H+
ArSO
ON ArS
O
ON
NO
NO
NO NO
ArSO
ON
NO
SulfametoxazolBactrim®, Trimetoprim-Sulfa ® - Urine infectionsCombi. with trimethoprime
NH2SO
OHN
NO
NH2SO
OH2N
Sulfonamides are acidic
Sulfanilamid pKa 10.4
NH2SO
OHN
- H+NH2S
O
OHN NH2S
O
OHN
Inhib. of folate reductase
H2NO
OH
PABA
H2N SO
ONH
RAntibact. sulfonamide
N
N NH
NOH
H2N
NH
OH
O
Dehydropteridinsyre
N
N NH
NOH
H2N
NH
NH
O
Dihydrofolic acid
CO2H
CO2H
N
N N
NOH
H2N
NH
NH
O
Folic acid
CO2H
CO2H
From diet, humans
N
N NH
HN
OH
H2N
NH
NH
O
Tetrahydrofolic acide
CO2H
CO2H
Folate-reduktase
Essential processesbacteria and animalsex. Thymin synthesis(Metab. CH3OH)
Trimetoprim
N
N
NH2
H2N OCH3
OCH3
OCH3
Quinolones
Inhib DNA-synthesis; DNA-gyrase (prokaryoter) uwounding DNA before replic..DNA-topoisomerase (humans), anticancer compds. ex. doxorubicinUnique mecanism, no cross resistanceBroad spectrum: G+ and G- ; also mycobactria, clamydia
N N
CO2HO
Parent comp.Nalidixic acid
Urinary tract infect. earliereffect on Gram-negative bacteria (ex. E. coli)
Moderne quinolones
N
OCO2H
R
FR
RR
F increase activity
Essentialt
Preferably HMust have aromatic ringcondenced with the pyridine
must be oxo
Chelater withCa2+, Mg2+, Zn2+, Fe2+, Fe3+, Bi3+
N
O O
O
N
OO
O
Met2+N
O OH
O
Intramolek.H-bond
pKa ca 5.5 - 6.5(Benzoic acid pKa 4.2)
CiprofloksacinCiprox®, Ciprofloxacin®Cilox®
N
CO2HO
N
F
HN
OfloksacinTarivid®
N
CO2HO
N
F
N O
N
OCO2H
R
FR
RR
(±)N
CO2HO
N
F
N O
Levofloxacin, 2x active
N
CO2HO
N
F
HN
Sparfloxacin
N
CO2HO
N
F
F F F
F
NH2
H2N
Trovafloxacin
Better effect on G+
OxazolidonesLinesolid Zyvoxid®
O N NO
O
F NH
O
Reg. Norge 2002, 1. antibact. drug with new mechaanism of action in 35 yearsInhib. protein synthesis early No cross resist.. G+ and some G-. Resistant strains
ON
O
HN
'R
RO
(S)-Konfig.
Essencial
R: H, CH3, OCH3, CHCl2'R: H, F
CH3O, CH3SO, Aryl, Hetroaryl, Mettet Hetrosykel
ON
O
HN
N
PNU 177553(Pharmacia&Upjohn)
F
S
SO
ON
O
OAZD 2563(AstraZeneca)
F
NO
FNHO
O
OH
New drugs?
initiator tRNA
OH 3'
tRNA-Met
O SO
NH2
tRNA-fMet
OS
O
HNO
mRNA30S ribosom
O SO
HNO
3'mRNA
5'
30S initiator kompleksAUG
50S ribosom
OS
O
HNO
3'5' AUG
Linesolid
NHCHO
3'
NH3+
5'
CO2-
mRNA
50S
O-fMet
30S
AA-OO-AA-FMet
Protein
AA'-O
70S
Other antibiotics
Antibiotics
Penicillines
β-Lactam-antibioticsLactam = cyclic amide
NO R
β-Laktam
NO R
α β
N
S
O CO2H
H H
NR
R'
Penicillins
NO
β-Laktamase-inhibitors
NO CO2H
H
Karbapenems
R
H R'
SR''
Cefalosporines
N
S
OCO2H
R''
HHN
R'
R
NO
H H
NR
R'
Monobaktames
SO3H
+ Cilastatin
N
S
O CO2H
H H
NR
R'
Gen. struct
β-lactam
N
S
1-Aza-4-tiabicykco[3.2.0]heptane1 2
3
456
7
tot. 7atoms in ring
(2S, 5R, 6R) [x.y.z]alkane
tot no. of atomesX atomsr
y atoms
z atomsr
N S
G -
G +N
S
CO2H
H
O
NH
R
O
HN
CO2HO
NH
R
O
HInhib. cell wall synth. - peptidoglycane≈ ala-ala
ala-ala
YX
YX
YX
YX X: N-acetylglucosaminY: N-acetylmuraminsyre
Pentapeptide:gly-gly-gly-gly-gly
Tetrapeptide:L-ala-D-glu-L-lys-L-ala
Peptidoglycane detail
Mechanism
N
SH
O
NH
R
O
YX
YX YX
YX
+
Peptidoglycane synth. -cross linking
trans peptidase
penicillin (≈ ala-ala)irreversible binding to trans peptidaseCross linking inhibited
enzyme
HNOH
H
O OHHN
SH
O
NH
R
O
enzyme
NOH
HO OH
Semi synthesis
Stability
N
S
CO2H
H
O
NH
OR
R=Ph: BenzylpenicillinR=OPh: Fenoksymetylpenicillinfrom fermentation
Penicillin amidase N
S
CO2H
H
O
H2N
6-aminopenicillansyre
R'COCletc. N
S
CO2H
H
O
NH
R'
O
N
S
CO2H
H
O
N
OHR
taut.
N
S
CO2H
H
O
N
ClR
Mild acidic hydrol
two amide func.Hydrolysis
iminochloride
PCl5
Basic amide hydrol. - ring strain in β-lactame
N
SH
O
NH
R
O
O OH
N
SH
O
NH
R
O
O OHOHHN
SH
O
NH
R
O
O OHOHPenicillosyre
stabile pH≥7
OH
H
Acidic hydrolysisAlternative A
OHNR
OPenilloaldehyde
+SH
H2N
O OH
Penicillamin
N
SH
O
NH
R
O
O OH
N
SH
HO
NH
R
O
O OHOH
HN
SH
O
NH
R
O
O OHO
Penicillosyre
labilem acidic media
H
SHN
O OH
HNR
O
Penillosyre
SH2N
O OH
HNR
O
SH2N
O OH
HNR
OOH2
+ CO2
±H
SHH2N
O OH
HNR
OOH
H
H2O
H
H2O
Acidic hydrolysisAlternative B
N
SH
O
NH
R
O
O OH
N
SH
O
NH
R
O
O OH
HN
SH
O OH
ONH
O
R
HN
SH
O OH
ONH
O
R
HO
PenicillosyreAs Alternative. AH
H2O
Acidic hydrolysisAlternative C
N
SH
O
NH
R
O
O OH
N
SH
O
NH
R
O
O OH
HN
SH
O OH
ONH
O
R
±HHN
SHH
O OH
ON
O
R H
HN
HS
O OH
ON
O
R
N
HS
O OH
ON
O
RH
N
HS
O OH
N
O HO
RS
NN
CO2H
CO2H
R
Penillinsyre
H
H
Structure acide stabile pennicillines
N
SH
O
NH
R
O
O OH
N
SH
O
NH
R
O
O OH
HN
SH
O OH
ONH
O
R
EWG R; Olessnukleofilic
N
H
O
NH
O
BensylP. acid labile
N
H
O
NH
OO
PhenoxymethylP.acid stabileIndictive electron withdrawing effect
H Nat. occuring P.
Semisynthetic, increased acid stability
NS
H
O
NH
O
O OH
HNN
O
N OO
PiperacillinTazocin®
N
SH
O
NH
O
O OH
NH2
HO
AmoxicillinAmoxicillin®,
N
SH
O
NH
O
O O
NH2
O OPivampicillinPondocillin®,
N
SH
O
NH
O
O OH
NH2
AmpicillinPentrexyl®,
HN
SH
O
NH
R
O
OHN
SH
O
NH
R
O
O OH
β-Lactamase
Larger R; effect on β-lactamase resistant bacteria (starical hindrance)
Resistant strains
N
SH
O
NH
R
O
O OHN
SH
O
NH
O
O OH
NO
Cl
CH3
KloksacillinEkvacillin®
N
SH
O
NH
O
O OH
NO
Cl
CH3
Cl
DikloksacillinDiclocil®
NS
H
O
NH
O
O OH
OCH3
OCH3
Meticillin
Acid labile, last resort drug resist. strains
N
SH
O
NN
O OHN
SH
O
NN
O O
O O
Semisynthetic, Broad spectrum, Imines
MeticillinamSelexid®
PivmeticillinamSelexid®
No nucleophiliccabronyl
β-Lactamase Inhibitors
Combination with penicillines
NO
H
OO OH
OH
NS
H
OO OH
NN NO O
Clavulanic acid Tazobaktam
N
X
R'
HR
OO OH
No subst, less steric hindrance
EnzymeOH
N
X
R'
HR
O OH
H
OO
Enzyme
H
N
OH
OO OH
OH
Clavulanic acid irreversibly inhibits β-lactamase
OH
HN
OH
O
O OH
OHHH
H HN
O
O
O OH
OH
O
Nu
Nu
O
Nu
H
HN
O
O
O OH
OH
O
HHNu
•Mechanism based irreversible enzyme inactivators Suicide substrate - kcat inhibitors - Trojan horse inhib. - latent alkylating agent ≈ Pro-drug, must be activated by the enzyme
Carbapenems / Carbapenins
NO CO2H
HH R'
SHO
NH
NO
MeropenemMeronem®
2. Gen.Not cleaved byDHP-1
Imipenem + cilastanTienam®
NO CO2H
H
R
H R'
SR''
No S in 5-membered ring
NO CO2H
HH R'
SHO
NH2Tienamycin fromStreptomyces cattleya1976Broad spectrumNot substr. for β−lactamase
Labile, acidic and basic media
Cleaved in vivo av DHP-I(dehydropeptidase I)
NO CO2H
HH R'
SHO
HNNH
Not nucleophilicm
Imipenem
HO S OHO
NH2
O
HN O
CilastatinDHP-I inhib.
Cephalosporins
Cefalosporin C from Cephalosporium acremonium 1945
N
S
OCO2H
HH
HN
HOONH2
O O
O N
S
OCO2H
R''
HHN
R'
R
6- membered ring; Less ring strain than penicillins
Subst in 3-pos., important for hydrolyttic stability
123
456
7 8
N
S
OCO2H
HHRHN
O
OOH
HN
S
CO2H
HO2C
RHNO
O+
Good leaving group
N
S
OCO2H
HHRHN
O
O
Metabolism
Esterase N
S
O
HHRHN
OH
O OH
N
S
O
HHRHN
O O
Inactive lactone
N
S
CO2H
H
O
NH
R
O mCPBA N
S
CO2H
HC
O
NH
R
O
(ox. av sulfidtil sulfoksid) Pummerer
omleiring
H
HH
O
N
S
HO2C
H
O
NH
R
O
OH
N
H
O
NH
R
O
S
CO2H
H
Δ
Semisynth from penicillins
Isolation from Cephalosporium sp
or semisynth from 7-aminocefalosporic acid (7-ACA)
N
S
OCO2H
HHH2N
O
O
7-ACA
1. generation: Relatively broad spectrum (G+, some G-)Cleaved by β-Lactamase
CephalexinCefalex® Keflex® N
S
OCO2H
HH
HN
O
H2N
Realtively diff. to hydrolyzeOnly oral Ceph.
N
S
OCO2H
HH
HN
O
O
O
S
CefalotinCefalotin® Keflin®
2. generation: More broad spectrumNot cleaved by β-Lactamase
CefoxitinMefoxitin®
CefuroximCefuroxim® Zinacef®
N
S
OCO2H
HO
HN
O
O
O
NH2
S
Increased stabilitycompared to cephalotin
Steric hindrance β-L
N
S
OCO2H
HH
HN
O
O
O
NH2
O
NO
Syn isomer, steric hindrance β-LAnti cleaved by β-L
3. generation: Very broad spectrum, also Pseudomonas sp Not cleaved by β-LactamaseAcid labile
CefotaximCefotaxime®Claforan®
CeftazidimFortum®
CeftriaxonRohephalin®
Good leaving groupSteric hindranceG-
N
S
OCO2H
HH
HN
O
O
O
N
S
N
H2N
O
N
S
OCO2H
HH
HN
O
S
N
S
N
H2NN
NN
OHO
O
Oral 3. gen (not in N):
N
S
OCO2
HH
HN
O
N
N
S
N
H2N
OHO2C
N
S
OCO2H
HH
HN
R
ON
S
N
H2N
OR'
R: -H, -CH=CH2, -CH2OCH3
Monobactams
NO
HN
SO3H
HN
O
NS
NH2
OHO
OMer stabil enn SulfacetinBare effekt på G-
AztreonamAzactam®
NO
H
HN
SO3H
ONH
HOO
O
NH2
O
From Sulfacetin; weak antibacterialNot substrate forr β-lactamase
NO
R'' R'''
NR
R' SO3H
Only 4 membered ring
Aminoglycosides
H2N
OO
Broad spectrum Toxic Inhib. protein synthesis ≈No absorb. from GI, local treatment infect. GI tract. Systhemic infections – parenteral adm.
Basic, water solubile salts phys. pH -Glykosides (= acetals) stabile acidic media because of protonated
amino subst.O
O
NH3
H
5' 3' mRNA
50S
30S
Ribosom
Protein
NH3+
NH3+
CO2-70S
Bind to mRNA read wrongTransloc. blocked
O
OH O
OO
HNOHOHHO
NHH2N
NH
H2NNH
HOO
NHHO
HO Streptomycin
N-Metylglucosamin
L-Streptose
Streptidin(sykloheksander.)
First aminoglyc.: Streptomycin (ca 1944) from Streptomycesgriseus
First antituberculosis drug. Toxic!
NeomycinStreptomyces fradia (1949).Maxitrol®, eyedropsLess tox. than streptomycin
GentamicinGaramycin®From Micromonospora purpurea.
TobramycinNebcina® Tobi®, TobrexStreptomyces tenebrarius.
NetilmicinNetilyn® injek.Semisynth from Sisomicin(Micromonospora inyoensis)
O
OHO
OHO
O
OH
NH2
NH2
HO
O
HONH2
NH2
OH
O
OH
NH2
H2N
Neomycin C
HO
O
O
NH2
NH2
O
NH2
NHR
R'
O
OHHN
HO
R = R' = -CH3: Gentamicin C1R = CH3, R' = -H: Gentamicin C2R = R' = -H: Gentamicin C1a
HO
O
O
NH2
NH2
O
NH2
NH2
O
OHH2N
HO
HOHO
Tobramycin
HO
O
O
NH2
NHO
OHHN
HO
O
NH2
OH
R
R = -Et: Netilmicin(R = -H: Sisomicin)
Lincomycines
Sulfur cont. antibiotics from Streptomyces lincolnensis; Naturally occuring: Linkomycin (not in N), more active semisynth
der. Inhib protein synth, binds to 50S part of ribosome
KlindamycinDalactin® Dalactin® Clindamycin®.
Semisynth from linkomycinNH
R'R
O
SOH
HOOH
N
O
R= H, R'=Cl: Klindamycin
R=OH, R'=H: Linkomycin,
Tetrasyclines
Chelate
Mechanism: Bindes to 30S part of ribosome, inhibits proteinsynth.; komplexing Mg2+ involved.
Binds also to 30S-rib. mammals, but bacteria cells also have activetransport mech. for T uptake.
The most broad spctrum antibiotic known to date. Bakteriostatic, not baktericid. Attacks natural bacteria flora in GI tract (oportunistic candida
infect.)
12
434a
565a6a
78
91010a 11a 12a
11 12
1 2
43
5678
910 11 12
Naftacene
O
OH
NHR2
O
N
OHHOOOH
R6H HR5
Tetracyclines: Gen. struct. (reg. in N.)
ABCD
ABCD
O
HO
R2HN
O
N
OHOH O OH
R6HHR5
Metn+
O
HO
R2HN
O
N
OHO O
OH
R6HHR5
2 Metn+
- 2 HO
OH
NHR2
O
N
OHOO
OH
R6H H
R5
Chelate: Chelos = Claw, Klo (greek)
Metn+ Ca2+ (milk)Fen+ (iron prep.)Al3+ (antacida.)
1 2
43
5678
910 11 12
O
OH
NHR2
O
N
OHHOOOH
R6H HR5
Acidic phenol Acidic enol
Basic amine
Zwitter ion (high water sol.)neutral pH
1 2
43
O
O
NHR2
O
N
OHHOOOH
R6H
R5H
Acid - Base prop.
Acidic enol
Stability; acid / base
O
OH
NHR2
O
N
OH
H
pH 2 - 6: Epimerisation C-4
HProtonated tetracycline
H Base
O
OH
NHR2
O
N
OH
H
H
O
OH
NHR2
O
N
OH
H
H
O
OH
NHR2
O
N
OH
H
H
O
OH
NHR2
O
N
OH
H
H
O
OH
NHR2
O
N
OH
H
HH
Epitetracycline≈ inactive
A
H
pH ≤2: Dehydratisation; Aromatisation C-ring (R6=OH)
OOH
HOH6
OOH
H2OH - H2O
OOH
HBenzylic cation(resonanse stab.)
OH OH OH OOH OH
Base
OHOH O
taut.CD
H
pH ≥7.5: Rearrangement to isotetracyclines (R6=OH)
OOH
OH6
OH
BaseH
OOH
OH
OH OOH
H
O
O
HOOH
H
O
O
5-ring lactone
OOH
H
O
O
Isotetracyclineinactive
CD H
TetracyclinIsolation from Streptomyces sp,Semisynth from chlorotetracycline more effective(low bioavailability)
O
OH
NH2
O
N
HOHOOOH
HOH H
Cl
Klortetracyclinfra fermenter. av Streptomyces arter
H2 / kat.
O
OH
NH2
O
N
HOHOOOH
HOH H
Tetracyclin
LymecyclinMore water sol., pro-drug.Semisynth from tetracycline
O
OH
NH2
O
N
HOHOOOH
HOH H
Tetracyclin
O
OH
NH
O
N
HOHOOOH
HOH H
Lymecyclin
NH
ONH2
OH
in vivo CH2O
H2N ONH2
OHLysin
1 2
43
5678
910 11 12
O
OH
NHR2
O
N
OHHOOOH
R6H HR5
TetracyclineOxytetracyclineDoxycyclineLymecycline
ABCD
R2R5 R6-H-H-H-CH2NHCH2NH(CH2)4CH(NH2)CO2H
-H-OH-OH-H
-OH-OH-H-OH
DoxycyclinNot OH i 6-pos. More stabile in water solution (also mixture).Longer t 1/2, good oral absorb.Semisynth oxytetracyclin.
O
OH
NH2
O
N
OHHOOOH
HOH H
Oxytetracyclin
OH
NCl
OO O
OH
NH2
O
N
OHOOH
HOH HOHNCS
Electrophilchrorination reag.
ClOH
O
OH
NH2
O
N
OHOOH
H HOH
ClOH
O
Hemiacetal
O
OH
NH2
O
N
OHOOH
H HOH
ClOO
OH
NH2
O
N
OHHOOOH
H HOHexocyclic double bond
H2 / kat.
O
OH
NH2
O
N
OHHOOOH
H HOH
- H2O- H2O
O
OH
NH2
O
N
OHHOOOH
HOH
O
OH
NH2
O
N
OHOHOH
HOH
O
Anhydrotetracyclin
HF
NaHSO3
Makrolides
Isolated from soil-bakteria, Streptomyces sp. Reletively narrow spectrum, mainly G+. Low tox. Bindes to 50S part of ribosome, inhib. Protein synth.
Structure / Activity: Macrolaktone (14-16-ring, smaller than antimycotic polyenes) Keto function No unsat. in lactone ring (spiramycin - dien) ≠ an timycotic
polyenes Amino sugar
Erytromycin
O
O
OO Amino sugar
O
O
O
HOO
ON
HO
Erytromycin
HOHO
O
OO
OHO
O
O
HOO
ON
OHOHO
O
OO
OHErytromycin ethylsuksinatePro-drug (masks bad tast)
O
OO
Ester hydrol. in vivo
Degradation acidic media
O
O
O
HOO
HOHO
O
R
R' O
O
HO
OO
HOHO
O
hemi-ketal
O
O
HO
O OHO
O
O
inactive spiroketal
Spiro-forbindelse
H H
-H2O
(Pretzels)
Klaritromycin
Increased stabil., bioavailability,less side effectsSomewhat more broad spectrum
Azitromycin
Increased stabil., bioavail.More active G- less active G+
In N. 2002. Ketolide.
Telitromycin
Spiramycin
IsolatedStreptomyces ambofaciens.G+.
O
O
O
MeOO
ON
HOHOHO
O
OO
OHIncreased stability acidic mediaNo intramolec. hemikatalisation
Increased stability acidic mediaNo intramolec. hemikatalisation
O
N
O
HOO
ON
HOHOHO
O
OO
OH
O
O
O O
O
OOH
N
OO
HOHO
O
OHOH
OR
R= H: Spiramycin IR=COCH3: Spiramycin IIR=COCH2CH3: Spiramycin III
No ketone
Increased stability acidic mediaNo intramolec. hemikatalisationImproved ribosome binding, less resistansIncreased ribosome affinity
O
O
N
OO
N
NN
O
MeOO
O
ON
HO
O
O
O
HOO
HOHO
O
R
R'
H
Erythromycin
Polypeptides Low oral avail.; local admin. or. infusion/injektion. Often high tox (kidneys). D-amino acids and other rare AA.
Vancomycin
Isol. Streptomyces orientalis (= Amycolatopsis orientalis).G+bakteria, Neisseria sp (G-).Inhib. Synth of mucopeptide polymer in cell wall.No oral uptake,Minimal degrad. In Gi, local treatment GI infect.Rel. tox., little resisenceSevere infections few other alternatives
Teicoplanin
Isol. Actinoplanes teichomyceticus.Only G+.Mech as vanoc.m..More lipid sol. than vancomycin, better distrib. In fat tissueLittle resistance tox. Less than vancomycin;Severe infect., few alternatives
OO O
Cl
ClOH
HO
O
HO OH
OHO
O
NH2
HO
NHO
HNN
H
O
OHOHHO
O
HNHO2C
O HN N
HO
OH2N
O HN
heptapeptide fragment
H2N CO2H
H R
D-Amino acid
H2N CO2H
R H
L-AA
OO O
Cl
ClO
O
HO OH
NHO
HNN
H
O
OHOHO
O
HNHO2C
O HN N
HO
ONH2
heptapeptide fragment
HO NH
R
O
HO O
O
OHHOOH
OH
OHOHO
NH
OH
O
R:
His
D-Phe
Ile
NH
HN
NH
HN
NH
HN
4LysO
Asp
D-Asp
OHNNH2
OHO2C
O NHN
O
HN
O
O
NH2Orn
O
ONHO
Ile
NHHO2C
D-Glu
HNO
LeuO
N
S
NH2Cys / Ile
O
HO NH2
CysNH2
SH
O
OH
Ile
BacitracinIsol. Baccilus subtilis.Mixt of struct(Bacitracin A, A1, B, C, D, E, F1, F2, F3 and G)Bacitracin A main comp. Bacimycin.Mainly G+.Inhib. Synth. mukopeptide in cell wall.Requires Zn2+ for activity
HN COCHNH
CH2CH2NH2
COHC
CH2
HN
CH2NHCO
CHNH
CHOHCH3
CO
CHNH
H2NH2CH2C
COCHH2NH2CH2CNH
OCCH(H3C)2HCH2CNHCO
CHR-H2C
OC C
H
CH2CH2NH2
NH
CO
CH
CHOHCH3
NH
CO
CH
NH
OC
CH2CH2NH2
CH2
CH2
CH2
CH2
CH
CH2CH3
CH3
R=-CH(CH3)2: Colisin A / Polymyxin E1R=Ph: Polymyxin B1
Colistin (Polymyxin E1)Polymixin B
OthersChloroamfenikol
O2N
H
H
OH
NHOH
OCl
Cl
Isol. 1.time Streptomyces venezuelae (1947), later found in severalmicroorg.
Broad spectrum. Inhib. Protein synth., mech. Not fullyunderstood.
Rel. tox. (daqmage bone marrow – an emiea, leukemi), seldomused systhemically.
Simple structure – total synthesis.
Fusidinic acid
Narrow spectrum: G+; Stafylloccocus aureus, corynebakteriaStreptococcus sp.(weak effect).
Inhib. Protein synth. No cross resist.
CO2H
OCOMe
HHO
H
HHO
Stereoid
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