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