Chemotherapeutic Agents, chapter 34-39

Antibacterial compounds (procaryotes) Antifungal compounds (eucarytotes) Antiparasitic agents (eucarytotes) Antiviral compounds

Anticancer compounds

Different living organisms

E u cary otes M ono or polycellu lar C ell nucleus; D N A M ay have cell w all sexua l a nd / or ase xual replication A n im als P lan ts Fungi P roto cista: - P rotozoea - A lgea

P roc aryo te s

B akteriea: M ono cellular, no nucleus - D N A sin gle strand, cell w all, asex. replic.

V iru s

R N A o r D N A + p ro tein coating (not re ally a cell) U se othe r ora m ism s rib osom e s for protein synth

Antibacterial compounds, chapter 34 (- antimycobacterials)

Synthitic 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

G+ and G- bacteria
Grampositive bakterier:
F. eks.

Gramnegative 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

Spirochetes - causes syphilis, lyme disease Neisseria- causes meningococcus, gonorrhea

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 space between 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.

Synthetic antibacterials (chemotherapeutica)

Antibacterial sulfonamides
A zo dyes B a yer etc Late 1800-centu ry, ex.
H O 3S N N N HO

S alvars an 1. an tis yphilis drug 191 2

H 2N HO As As OH NH2

M e tylo ran g e S c reening of d yes as a ntibacte rials

O 2N

N N

P arar d t

1 932: P ro n to cil active against S tre ptoc cocc es infec tio n n o ac tivity on bac terial c ultures
O H 2N S O H 2N N N NH2

193 5: P ronto cil m etab iliz ed (a zore duc tase ) to S u lfan ilam id in viv o
O H2N S O NH2

(rel. tox isk )

M o dern s ulfa d ru gsr

O H R N S O NH2

R : A ryl or hetro aryl

S u lfo n a m id e s a re a c id ic
O H 2N S O NH2

- H+

O HN S O

NH2

O HN S O

NH2

O HN S O

NH2

S u lfa n ila m id p K a 1 0 .4

Nytral sulfonilamid drlig vannlselig. Urine pH ca 6: Crystallization neutral form, kidney damage Modern sulfa drugs pKa 5 7; better solubility

Sulfametoxazol
O N O HN S Ar O O N O N S Ar O O O O N O N S Ar O N O N S Ar O

-H

Bactrim, Trimetoprim-Sulfa Urine infections Combi. with trimethoprime

O N

Sulfametoksasol pKa 6.1

N O N S Ar O

O HN S O

NH 2

O OH N H 2N N N N C O 2H O OH N H 2N N N N H N H OH N H NH C O 2H

A n tib act. su lfo n am id e

H 2N O H 2N OH O R S NH O

F o lic acid

F rom diet, h um ans

PABA
O OH N H2N N H N N H

D eh yd ro p terid in syre
O NH N H C O2H

F olatereduktase
H 2N

OH N N N N H N H

NH C O2H

C O2H

C O 2H

T etrah yd ro folic acid e

T rim eto p rim

NH2

D ih y d ro fo lic acid
OCH3

E ssential p rocesse s b acteria and anim als e x. Th ym in synthesis (M etab. C H 3 O H )

N H 2N N

OCH3 OCH3

Inhib. of folate reductase

Trimetoprim

Quinolones
Inhib DNA-synthesis; DNA-gyrase (prokaryoter) uwounding DNA before replic.. DNA-topoisomerase (humans), anticancer compds. ex. doxorubicin Unique mecanism, no cross resistance Broad spectrum: G+ and G- ; also mycobactria, clamydia

P a re n t co m p . N a lid ix ic a cid
O C O 2H N N

M o d e rn e q u in o lo n es m u st b e o xo F in cre a se a ctivity
F R N R R O C O 2H

U rin a ry tra ct in fe ct. e arlie r e ffe ct o n G ra m -n e g a tiv e b a cte ria (e x. E . co li)

E sse n tia lt P re fe ra b ly H

Intram olek. H -bond

O H O O N

M u st h a ve a ro m a tic rin g co n d e n ce d w ith the p yrid in e

C helater w ith C a 2 + , M g 2+ , Z n 2 + , F e 2 + , Fe 3+ , B i 3 +
N O O O

M et 2 +
O O O N

pK a ca 5.5 - 6.5 (B enz oic acid p K a 4.2 )

R F R R

O CO 2 H N R

Ciprofloksacin Ciprox, Ciprofloxacin Cilox

O F N HN N CO 2 H N N F

Ofloksacin Tarivid
O CO 2 H O N O N N O F C O2H

L e vo flo xacin , 2x active

()
S p arflo x acin
NH2 O F N HN F N H 2N CO 2H F N F N F

T ro vaflo xa cin
O CO 2H

B etter effect on G +

Oxazolidones
Linesolid Reg. Norge 2002, 1. antibact. drug with new mechaanism of action in 35 years Inhib. protein synthesis early No cross resist.. G+ and some G-. Resistant strains
CH 3 O, CH 3 SO, Aryl, Hetroaryl, Mettet Hetrosykel Essencial
O

Zyvoxid
O O N F N O NH O

'R: H, F

'R

O H N O R

R: H, CH

3,

OCH 3 , CHCl

New drugs?
O O S N F N O O H N F N HO OH N F O O O N O

(S)-Konfig.

PNU 177553 (Pharmacia&Upjohn)

AZD 2563 (AstraZeneca)

O NH 2 OH 3' O O S O O HN O S O HN

Linesolid
HN S O O

mRNA 30S ribosom

50S ribosom

5' initiator tRNA tRNA-Met tRNA-fMet

AUG 30S initiator kompleks

3' mRNA

5'

AUG

3'

AA'-O NHCHO O-AA-FMet AA-O O-f Met

5' 3'

mRNA

Other antibiotics

50S 70S Protein 30S

CO 2 -

NH 3 +

Antibiotics

F-Lactam-antibiotics
Lac tam = cyc lic a m ide
O R N

F-Lakta m
O R N

E P en icillin s
R' N R O N S H H C O2H

F C efalo sp o rin es
R' N R O N H H C O 2H R '' S

F-L a ktam asein h ibito rs

O N

K a rb ap en em s
O N R H H R' C O 2H R '' S

M o n o b aktam e s
O R' N R N H H S O3H

+ C ilastatin

Penicillines
G en. struct
7 1 2 3

N
5

1-A za-4-tiabicykc o[3.2.0]h epta ne

R' N R

O N

C O 2H

S
4

S H H

tot. 7ato m s in ring

F-la ctam (2S , 5R , 6R ) X atom s r z a tom sr

[x .y.z]a lkan e tot no . of atom es y atom s

M ech a nism H Inhib. cell w all s ynth. - peptidog lyc ane - ala -ala
O O R N H O O R N H N H N S H C O 2H X Y C O 2H X Y

P ep tid ogly cane d etail

G+
X Y

X : N -ace tylglucosam in Y : N -ace tylm ura m insyre P enta peptide: gly-gly-g ly-gly-gly

ala-ala

T etrapeptide : L-a laD -gluL-lysL-a la

G-

P e p tid o g lyca n e syn th . -c ro ss lin kin g

X Y X Y

p e n icillin (- ala -a la )irre ve rs ib le b in d in g to tra n s p e p tid as e C ro s s lin kin g in h ib ite d e n zy m e tra n s p e p tid a se
O HN H H O O R N H N S H R O OH O H O O N H HN S H

e n zy m e
N H O OH

+
X Y X Y

Semi synthesis
tw o am ide fun c. H ydro lys is
O O R N H N S H C O 2H

P enicillin am id ase

O N H 2N

C O 2H

R 'C O C l etc.
R'

O O N H N

CO 2H S H

S H

R = P h: B enzy lpenicillin R = O Ph : Fe no ksy m etylpen icillin from fe rm entation taut.

O OH R N N S H C O 2H

6-am in openicillansyre M ild acidic hyd rol

C O 2H N N S H

P C l5
R

O Cl

im inoch lorid e

Stability
B asic am ide hydrol. - ring s train in F-lac tam e OH
O O O R N H N S H R O N H OH O OH N S H O OH OH HN S H O OH

H
O R

O N H

Pe nicillo syre

s tabile pH 7

A cidic h ydrolysis A lternative A H 2O H

O O R N H N S H R O OH HO O N H OH N S H R O N H O OH O

P en icillo syre
H O HN S H R O OH

P en illo syre
O HN H N O S OH

labilem a cidic m edia H

O OH O H 2N R O H N SH OH R O OH O OH O H2N H N S OH2 H 2N R O H N

+ CO2

R O

H N

+
O

H 2N SH

OH

P en icillam in

P en illoa ld eh yd e
A cidic hyd rolysis A lternative B
O O O R N H N S H O OH

H 2O

H 2O
O HN

OH O HN HO O NH R

OH

S NH H

S H

H O
O O R N H N S H

OH

A s A lterna tiv e. A

P en icillo syre

A cidic h ydrolysis A lternative C

O O O R N H N S H O NH H OH O HN S O OH O HN S H H N R H O N R O S H R N N CO 2H S C O2H R O O N H N HS O OH O N R H O N HS OH O OH O HN HS O OH

H O
O O R N H N

OH

P en illin syre

S tru ctu re ac ide stab ile pen nicillines

O O O R N H N S H O HN S NH R O S H N H H H O O N O OH O OH O OH O N H N H

B ens ylP . ac id labile

H O
O O R N H N

Nat. occuring P.

E W G R ; O lessn ukle ofilic

P henoxym eth ylP .acid stabile Indic tive ele ctron w ithdraw ing effe ct

Semisynthetic, increased acid stability Piperacillin Tazocin

OH

Ampicillin Pentrexyl,
O O N H N H

Amoxicillin
O O O N O S H N O O N H N S H OH

S HO

Amoxicillin,
O O O N H N H OH

NH 2

Pivampicillin
O

O N N H H S

O O O NH 2

Pondocillin,
NH 2

R esista nt strain s
O O O R N H N S H R OH OH HN S H O O O O R N H N S H OH N O CH 3 Cl O O N H N H S

F-Lac tam ase

O O N H

Kloksacillin Ekvacillin
OH

L arger R ; e ffect on F-lac tam a se resis tan t bacteria (staric al hindrance )

Dikloksacillin Diclocil
O Cl N O CH 3 Cl O O N H N H S OH

Meticillin
O O OCH 3 O N H OCH
3

OH

N S H

Acid labile, last resort drug resist. strains

Semisynthetic, Broad spectrum, Imines

Meticillinam Selexid
O O N N N H S OH

Pivmeticillinam Selexid
O O N N N H S O O O

No nucleophilic cabronyl

F-Lactamase Inhibitors
Combination with penicillines Clavulanic acid
E nzym e
OH O O N X H OH R' R

Tazobaktam
O O N OH N N N

E nzym e
O O N

OH R' R

O O N O H

OH

N o subst, less steric hindrance

X H H

OH

S HO O

Mechanism based irreversible enzyme inactivators Suicide substrate - kcat inhibitors - Trojan horse inhib. - latent alkylating agent Pro-drug, must be activated by the enzyme
C lavu lan ic acid irreversib ly inhib its F-la ctam ase
OH O N O H Nu OH O OH O H H Nu O HN O Nu OH H O HN O OH O OH O O HN O Nu OH OH

H H

O O

OH

HH

Carbapenems / Carbapenins

O N R H H

C O 2H R '' S R'

T ien a m y c in fro m S tre p to m yce s ca ttle ya 1976 B ro a d sp e ctru m N o t su b s tr. fo r Fla cta m as e
HO

O N H H

C O 2H S R'

NH2

L a b ile , a c id ic an d b a sic m e d ia C le a ve d in vivo a v D H P -I (d e h yd ro p e p tid a s e I)

N o S in 5 -m e m b e re d rin g

Imipenem + cilastan Tienam

NH O N HO H H R' C O 2H S HN NH2 HN S O O OH O

Meropenem Meronem
O CO 2 H N HO H H R' S N NH O

N ot nucleophilicm

HO

Im ipe n em

C ilastatin D H P -I inhib.

2. Gen. Not cleaved by DHP-1

Cephalosporins
C efalo spo rin C from C ephalosporium ac rem o niu m 19 45
C O 2H O HO NH2 O O H N N H H S O O C O 2H O 6 5 4 R '' R' N 3 N 2 R 7 8 S H H 1

6- m em bered ring; Less ring strain th an pe nicillins S ubst in 3-pos., im portant for hyd rolyttic stability

OH

C O 2H O RHN H H S N O

O H O 2C RHN HN

C O 2H

+
S O

G o o d leav in g g ro u p

M e tab o lism
C O 2H O RHN H H S N O O O OH O N H H S OH RHN H H S O N O O RHN

E sterase

In ac tive lac to n e

Isolation from C ep halosporium sp or sem isyn th from 7 -am in o cefalo sp o ric acid (7-A C A )
C O 2H O H2N H H N S O O

7-A C A

S em isy nth fro m p enicillin s

H O 2C H O R O N N H S H C O2H

m CPBA
R

O N N H S H O

C O 2H

(
C H H H R

O N N H S H OH C O 2H O R O N N H H S

(ox. av sulfid til sulfoksid)

P um m erer o m leiring

1. generation:

Relatively broad spectrum (G+, some G-) Cleaved by F-Lactamase

C O 2H H 2N O O H N N H H S

Cephalexin Cefalex Keflex

Cefalotin Cefalotin Keflin

S O

C O 2H O H N N H H S O

R ealtively d iff. to h yd ro ly ze O n ly o ral C ep h .

2. generation:

More broad spectrum Not cleaved by F-Lactamase

Cefuroxim Cefuroxim Zinacef

Cefoxitin Mefoxitin
C O 2H H N S O O N O H S O O NH2

S yn iso m er, steric hindran ce F-L A nti clea ved b yF-L

C O 2H H N O O N H H S O O NH2

Increased stability com p ared to cepha lotin

O

O N

S te ric hindranc e F-L

3. generation:

Very broad spectrum, also Pseudomonas sp Not cleaved by F-Lactamase Acid labile
Ceftazidim Fortum
C O 2H O O N S H 2N N O S H O 2C O H N O N H H S

Cefotaxim Cefotaxime Claforan

O N N H 2N O S H N O

G o o d lea vin g g ro u p S teric h in d ran c e G-

N H H

CO2 N

Oral 3. gen (not in N):

Ceftriaxon Rohephalin
O N N H 2N O S C O2H H N O N H H S O N S N N OH N H2N O S R' O N H N O N H H C O 2H R S

R: -H, -CH=CH2, -CH2OCH3

Monobactams
O R' N R N SO 3H

F rom S u lfa cetin ; w ea k a ntibac terial N ot su bstra te forr F-lactam ase

O HO O H N O S O3H

R '' R '''

O NH2 N H

N O H

O nly 4 m em bered ring

NH 2

Aztreonam Azactam
HO

S N O N O H N O H O N SO 3 H

Mer stabil enn Sulfacetin Bare effekt p G-

Aminoglycosides
 Broad spectrum  Toxic  Inhib. protein synthesis  -N o absorb. from GI, local treatment infect. GI tract.
 Systhemic infections parenteral adm.
H 2N O

O NH3 O

 Basic, water solubile salts phys. pH  -Glykosides (= acetals) stabile acidic media because of protonated amino subst.

Bind to mRNA read wrong Transloc. blocked

5' 3'

NH 3 +

mRNA

50S Protein 30S Ribosom 70S

CO 2 -

NH 3 +

NH H 2N NH H 2N O HN O OH O NH HO O NH OH OH

Streptidin (sykloheksander.)

 First aminoglyc.: Streptomycin (ca 1944) from Streptomyce griseus  First antituberculosis drug.  Toxic!

L-Streptose
HO HO HO O

Streptomycin

N-Metylglucosamin

Neomycin Streptomyces fradia (1949). Maxitrol, eyedrops Less tox. than streptomycin
NH 2 O HO HO O O O H2N NH 2 NH 2 HO O OH OH NH 2 O NH 2

Gentamicin Garamycin From Micromonospora purpurea.

R' NH O NH 2 O

Netilmicin Netilyn injek. Semisynth from Sisomicin (Micromonospora inyoensis)

OH O

NH 2

HO O OH NH 2
NH 2 O HO O OH N H R NH 2

HO HN

Neomycin C

OH OH

R = R' = -CH 3 : Gentamicin C 1 R = CH 3 , R' = -H: G entamicin C R = R' = -H: Gentamicin C 1a

HO HN

R = - Et : Netilmicin (R = -H: Sisomicin )

NH 2 O HO NH 2 O NH 2

Tobramycin Nebcina Tobi, Tobrex Streptomyces tenebrarius.

HO HO

HO O OH NH 2

O H2 N

Tobramycin

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

Klindamycin Dalactin Dalactin Clindamycin. Semisynth from linkomycin

N O

R NH HO

R'

R = H , R '= C l: K lin d am ycin R = O H , R '= H : Lin ko m ycin ,

OH

O S OH

Tetrasyclines
OH
10 9 8 7

O HO
11 12

OH O
1 2 3 4

O NHR2 OH

 Mechanism: Bindes to 30S part of ribosome, inhibits protein synth.; komplexing Mg2+ involved.  Binds also to 30S-rib. mammals, but bacteria cells also have active transport mech. for T uptake.  The most broad spctrum antibiotic known to date.

D
6

C
R6

B
H5 R5 H

A
N

T etra cyclin es : G en . stru ct. (re g. in N .)

10 9 8 7 11 12 1 1 1a 1 2a

10a 6a

C
6 5a

B
5 4a

A
4

2 3

 Bakteriostatic, not baktericid.  Attacks natural bacteria flora in GI tract (oportunistic candida infect.)

N aftac en e

Chelate
N HO R 2H N N H R5 H R6 O O OH O O OH H R5 H R6

A cid - B as e p ro p .
A cidic ph enol A cid ic en ol Zw itter ion (h igh w ater so l.) neu tral pH O HO
11 12

HO R 2H N O O

OH
10 9 8

OH O
1 2 3

O NHR2 OH A cidic en ol

M e tn +
OH O OH OH

M et n +
OH O O O HO O NHR2 R6 H R5 H OH N

OH

O HO

OH O
1 2 3

O NHR2 O

-2H

C he late: C h elos = C la w , K lo (g ree k) M et n + C a 2 + (m ilk) F e n + (iro n p re p.) A l 3 + (an ta cida .)

R6

H5

R5

R6 B as ic am in e

R5

N H

Stability; acid / base

p H 2 - 6 : E pim e ris a tio n C -4 O HO O NHR2 OH N H H O HO O NHR2 O HO O NHR2 H N H OH H N H O HO O NHR2 OH H N H O HO

O NHR2 OH

A
H

B ase

H N H

OH

P rotonate d tetrac ycline

H
O HO O NHR2 H N H OH H

E pitetra cyc line - inac tive

p H 2 : D eh yd ratis ation ; A rom a tis atio n C -rin g (R 6 =O H ) OH O OH OH O OH OH O OH OH O OH OH OH O

D
6

C
HO H

H 2O

- H 2O

B ase
H

taut.

B enzylic cation (res onans e stab.)

p H 7 .5: R earra n g e m e nt to iso tetracyclin es (R 6 =O H ) OH O OH OH O OH OH O O H H O H OH O O H H O OH O O H O

D
6

C
O

B ase

5-rin g lacton e

Isotetracycline in active

R5 T etrac yclin e -H -O H -H O xytetracyclin e -O H D o xyc yclin e L ym ec yclin e

R6 -O H -O H -H -O H

R2 -H -H -H
9 8

OH
10

O HO
11 12

OH O
1 2 3 4

O NHR2 OH

D
7 6

C
R6

B
H5 R5 H

A
N

-C H 2 N H C H 2 N H (C H 2 ) 4 C H (N H 2 )C O 2 H

Tetracyclin Isolation from Streptomyces sp, Semisynth from chlorotetracycline more effective (low bioavailability)
OH O HO HO O O NH 2 Cl HO H H OH N HO OH O HO HO O O NH 2 H H OH N

H 2 / kat.

Klortetracyclin fra fermenter. av

Streptomyces

arte r

Tetracyclin

Lymecyclin More water sol., pro-drug. Semisynth from tetracycline

OH O HO HO O O N H HO H H OH N N H NH 2 O OH HO OH O HO HO O O NH 2 H H OH N H 2N Lysin

in vivo

CH 2 O
NH 2 O OH

Lymecyclin

Tetracyclin

Doxycyclin Not OH i 6-pos. More stabile in water solution (also mixture). Longer t 1/2, good oral absorb. Semisynth oxytetracyclin.
OH O HO OH O O NH2 HO H H OH N OH O Cl N O OH O OH Cl O OH O NH2 OH O OH Cl O H H OH N O OH O NH2 OH

O x y tetra c yc lin

NCS E le ctro phil c hrorin ation re ag . - H 2O

HO

H OH N

OH

H em ia c etal HF

- H 2O
OH OH O HO O O NH2 H OH N OH

OH

O HO

OH O

O NH2

OH

O Cl

NaH SO 3

O HO

O NH2

e xo c yc lic d oub le b on d
O OH NH2 OH H

H OH N

OH H H OH N

OH

H 2 / k at.
OH OH O OH O O HO OH O O NH2 H OH N OH

H OH N

A nh ydrotetrac y clin

Makrolides
O O O O Am in o sugar

 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 N HO HO HO O O O O O OH O HO O HO HO O HO O O O O O OH O O N O O O

D eg ra d a tio n ac idic m e d ia H
O HO HO O O HO O R HO HO O O

H
HO O

h em ike ta l
O HO

HO O O O O

E ster hydrol. in vivo

O O

O R'

-H 2 O
O

E rytrom ycin

E rytrom ycin ethylsuks inate P ro -drug (m asks bad tast)

ina ctive s p iro ke ta l

S p iro fo rb in de ls e

Azitromycin
E ry th ro m ycin H
O HO HO HO O O O R HO HO M eO O O O O O OH

Klaritromycin
N O N O HO O HO HO HO O O O O O OH O HO O N

O R'

In cre a s ed sta b ility a cid ic m e d ia N o in tra m o le c . he m ik a ta lisa tio n

Incre ased stab ility acid ic m e dia N o in tram ole c. hem ika talisation

Telitromycin
N N N

Increased stabil., bioavailability, less side effects Somewhat more broad spectrum

Increased stabil., bioavail. More active G- less active G+ Spiramycin

OH OH

O N N O O O O O O O O R M eO O HO O O O

IsolatedStreptomyces ambofaciens. G+.

O

N o k e to n e
O N OH O O HO O HO

Incre ased stab ility acid ic m e dia N o in tram ole c. hem ika talisation Im proved ribosom e binding, le ss resistans Incre ased rib osom e affinity

R = H : S p ira m ycin I R = C O C H 3 : S p ira m ycin II R = C O C H 2 C H 3 : S pira m ycin III

In N. 2002. Ketolide.

Polypeptides
 Low oral avail.; local admin. or. infusion/injektion.  Often high tox (kidneys).
 D-amino acids and other rare AA.
H H 2N R C O2H R H 2N H C O 2H

D -A m in o a cid

L -A A

Vancomycin
HO

NH2

HO OH O O O O O OH Cl Cl OH

Teicoplanin
HO OH HO O OH O O O O HN H O 2C N H Cl H N O O N H H N O O O N H NH2 O HO HO O O NH N O H

R:
O R Cl

HO O O HN H O 2C HO N H

H N O

O N H H 2N O

H N O

O N H

H N

OHOH

hep tape ptide fra gm en t

HO O OH O OH OH

HO

h epta pe ptid e frag m en t

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 resisence Severe infections few other alternatives

HO

OH Isol. Actinoplanes teichomyceticus. Only G+. Mech as vanoc.m.. More lipid sol. than vancomycin, better distrib. In fat tissue Little resistance tox. Less than vancomycin; Severe infect., few alternatives

D-Asp

O NH 2 N O N H NH

Bacitracin Isol. 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
HO 2 C

HO 2 C HN

Asp

His
O HN

HN O

D-Phe
NH

Lys

O O HN N H

HN

Ile
O

Ile
SH HO O NH 2 O NH 2

D-Glu O

NH NH O H N O S N

Orn
NH 2

OH

Leu

NH 2

Cys

Ile

Cys / Ile

Colistin (Polymyxin E1) Polymixin B

HN CO R -H 2 C CH CH CH 2 CH 2 NH 2 CO NH CH 2 CH 2 NH 2 CH 2 CH 2 NH 2 NH CO CH 3 H O O N C C N C CH N C C N C C C C C C CH 2 CH 3 (H 3 C) 2 HCH 2 C CH HC H H O H O H H H2 H2 H2 H2 H OC CH 2 CHOHCH 3 NH CH 2 H 2 NH 2 CH 2 C CH NH R=-CH(CH 3 ) 2 : Colisin A / Polymyxin E 1 CO CO R=Ph: Polymyxin B 1 NH CH CHOHCH 3 H 2 NH 2 CH 2 C CH NH C O

Others
Chloroamfenikol

Cl O 2N O H H OH NH OH Cl

 Isol. 1.time Streptomyces venezuelae (1947), later found in several microorg.  Broad spectrum. Inhib. Protein synth., mech. Not fully understood.  Rel. tox. (daqmage bone marrow an emiea, leukemi), seldom used systhemically.  Simple structure total synthesis.

Stereoid
HO H CO 2 H OCOMe

Fusidinic acid  Narrow spectrum: G+; Stafylloccocus Streptococcus sp.(weak effect).  Inhib. Protein synth.  No cross resist.

H HO H

aureus,

corynebakteria