ANTIBIOTIKA

(R )

3HC

H
N

H2
C

(R )

C
C
O H 3C H

(Z )

H
C

N
H

CH3 O

Hari Purnomo
R1

HO

NH

CO2 C
CH R

C
N
H

Ar
C
H

H
R3

(R )

OH
14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

Penggolongan :
A. Antibiotika laktam

a. Sefalosporin kla sik

b. Pra- Sefalosporin
c. Sefamis in
d. Oksasefem

1. Turunan Penisilin
2. Turunaan Sefalosporin
3. Turunan laktam Non Klasik
B. Turunan Amfenikol
C. Turunan Tetrasiklin
D. Turunan Aminoglikosida
E. Turunan Makrolida
F. Turunan Polipeptida
G. Turunan Linkosamida

a.
b.
c.
d.
e.

Turunan asam amidinopenisilanat

Turunan asam penisilanat
Karbapenem
Oksapenem
Turunan laktam Monosiklik

H. Turunan Polien
I. Turunan Ansamisin
J. Turunan Antrasiklin
K. Fosfomisin
14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

Penggolo ngan Berdasarkan Mekanis me

Kerja

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

TheActionofAntimicrobialDrugs

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

5
Figure 20.2

1. Inhibition of Cell Wall Synthesis

:Penicillin, bacitracin,
cephalosporin, Vancomisin

Pe ni ci l l i ns and Cephal ospor i ns

O

CH3

S
NH
O

CH

CH

basitrasin

C
CH3
CH

COOH

Penicillin nucleus

B-lactam ring
O

S
R

NH
O

CH

C H2

C
C

O
CH2

C
CH3

Cephalosporin nucleus
14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

Cellwallstructure
Gramnegative

Grampositive
Pennicilinbindingprotein(PBP)
14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

Cellwallstructure

14022007:09.0010.40

Gramnegative

HariPurnomo,ANTIBIOTIKA,FARKIMII.

Cellwallstructure

Grampositive

Pennicilinbindingprotein(PBP)
14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

Spectrumofantimicrobialactivity
NarrowspectrumdrugsaffectonlyGram
positivecellsoronlyGramnegativecells.
BroadspectrumdrugsaffectbothGrampositive
andGramnegativecells.
Thenormalfloraisaffected,too.

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

10

Fig.131

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

11

AntibioticTarget1:CellWall
Cell wall is pep tido gl ycan , a repeating polymer of disaccharide,
tetra-peptide repeats cross-linked into a 3D matrix

-lactam antibiotics interfere with cell wall biosynthesis of

Gram-positive bacteria (Staphylococci, Streptococci)
- weakened PG cellHariPurnomo,ANTIBIOTIKA,FARKIMII.
wall = cells pop from osmotic shock

14022007:09.0010.40

12

AntibioticTarget1:CellWall

Bacterial tr ans peptidase enzyme forms crosslinking amide bonds

between #3 L -Lysi ne and #4 D -Alani ne residues
TPase cuts off #5
D-Ala residue,
then links L-Lys
side chain to the
remaining D-Ala

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

13

lactams:MechanismofAction
-lactams inhibit transpeptidase by mimicking its substrate,
the terminal D-AlaD-Ala
Transpeptidase attacks the -lactam ring of penicillin, forms a
covalent bond that is slow to hy dr olyze ; enzyme is deactivated

Normally, the enzyme forms a temporary bond with D-Ala that

is rapidly broken by the side chain of Lysine
14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

14

Bakteri..Dindingselbakteri..Peptidoglikan
SintesisPeptidoglikanada3tahap:
TahapI:PembentukanUDPNAcMurpentapeptida
TahapII:Pembentukanakseptordekapeptidamid
TahapIII:Pembentukanpeptidoglikan(salahsatu
bahanbakuDAlanilDAlanin)
(Penisilin,sefalosporinbekerjapadatahapini)

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

15

Penicillins and Cephalospo

O

CH3

S
NH
O

CH

CH

C
CH3
CH

COOH

Penicillin nucleus

B-lactam ring
O

S
R

NH
O

CH

C H2

C
C

O
CH2

C
CH3

Cephalosporin nucleus
14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

16

Peni c i l l i ns
O
R

CH3

S
NH
O

CH

CH

C
CH3
CH

COOH

B-lactam ring

Common nucleus
14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

17

.History
AlexanderFleming(1928)
InEngland,noticedthatS.aureusdidnotgrow
aroundacolonyofmoldonagar
ThemoldwasPenicilliumnotatum.
Heisolatedtheinhibitorysubstance.Calledit
penicillin.
Penicillinwasunstable.

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

18

 FloreyandChain(1940)
InEngland
Resumedstudyofpenicillin
Isolatedandpurifiedpenicillin
USAbecameinvolved
PenicillinusedduringWWII

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

19

 Penicillinisanantibiotic.
Antibioticisfromantibiosis,meaningagainst
life.
antibioticAsubstancethatisproducedbyone
microorganism(abacteriumorfungus)thatkills
orinhibitsthegrowthofanothermicroorganism.

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

20

 Majorproducersofantibioticsdiscovered
throughouttheyears:
Molds
Penicillium
Cephalosporium
Bacteria
Streptomyces
Bacillus
14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

21

(a)Penicillins

Natural(PenG,PenV[oral])
bestvs.G+
betalactamaseresistant,butloweractivity
nafcillin,oxacillin,methicillin
expandedspectrum(G+andG)
ampicillin,piperacillin,mezlocillin,
ticarcillin
acidresistant(oral)
amoxycillin,PenV,oxacillin

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

22

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

23

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

24

Penicillins
O

Penicillin G

CH2

NH
O

Penicill in V

Ampicillin

CH2

CH

CH3

S
CH C H

CH

CH3
COOH

Common nucleus

Common nucleus

NH2
14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

25

R=

CH2
Benzil penisilin ( Penisilin G )

R=

OCH2
Fenoksimetilpenisilin
( Penisilin V )
NH2

R =

CH
A m p is ilin

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

26

NH2
CH

R=

Amoksisilin

HO
OCH3
Metisilin

R=
OCH3
Cl
R=

14022007:09.0010.40

CH
HN

Kloksasilin

HariPurnomo,ANTIBIOTIKA,FARKIMII.

27

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

28

H 3C

OH

OH

(S )

(S )

H 3C

H
H

(R )

H
(S )

(R )

N'

N "H

N'

14022007:09.0010.40
Penisilin

R
HariPurnomo,ANTIBIOTIKA,FARKIMII.

DAlanilDAlanin

29

StabilitascincinLactam

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

30

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

31

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

32

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

33

DegradasidenganLactamase

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

34

DegradasidenganLactamase

S
N

H O
X

H
N

C
O

OH

H O
X

C
O

OH

E nzim

14022007:09.0010.40

HN

E nzim

HariPurnomo,ANTIBIOTIKA,FARKIMII.

35

Resistance:lactamaseEnzymes

Bacteria produce enzymes to hydr olyze the -la ctam r ing

before
drugs
can reach inner membrane
where PG synthesis occcurs
14022007:09.0010.40
HariPurnomo,ANTIBIOTIKA,FARKIMII.

36

Resistance:lactamaseEnzymes

A cell may produce 100,000 lactamase enzymes, each of which

can destroy 1,000 penicillins per second
100 million molecules of drug destroyed per second
14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

37

OvercominglactamResistance

(resistance)

slow to
hydrolyze

(cell wall enz.)

Aug menti n combines -lactam antibiotic w/ cla vula nat e, a

suic id e -lactam that occupies the -lactamase enzymes
- Allows active drug (amoxacillin) to reach target enzymes,
PG-synthesizing transpeptidases lining the inner membrane
14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

38

ResistenLactamase

Lesstolerancetothesterichindrancenearthesidechainofamidabond.
Attacheddirectlytothesidechaincarbonylandbothorthopositionaresustitutedby
methoxyresistant
MovementofoneoftheOCH3toparaposition,puttingmethylenbetweenthearomatic
ring6APAsensitif
ResistanttoenzymedegradationbasedondifferentialSterichindrance
14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

39

Stabilitasterhadapasam

Stabilitasterhadapasam

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

40

O
O

H
H 2C

C
H

(S )

H
(R )

(S )

(S )

N'

N "H

OH

H
C

CH3

(R )

N'
O

Cephalo spori ns
14022007:09.0010.40

DAlanilDAlanin

R
HariPurnomo,ANTIBIOTIKA,FARKIMII.

O
41

(b)Cephalosporins(lesssensitivetobetalactamases)
1stgen:G+action
cephalexin,cephalothin,cefazolin

2ndgen:G+andGaction,includingBacteroides,but
notPseudomonas
cefaclor,cefuroxime,cefoxitin

3rdgen:Gmostly,includingPseudomonas
canpenetratetheCNS,socanbeusedformeningitis
ceftazidime,cephotaxime,cephoperazone

4thgen:slightlyexpandedspectrum
cefepime,cefirome

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

42

(c)monobactamsmonocyclicbetalactamring,soresistantto
betalactamases
effectivevs.Gonly,notG+oranaerobes
aztreonam

(d)carbapenems
broadspectrum(G+andG),butmaybetoxic
imipenem,meropenem(reducedtoxicity)

SideEffects(ofbetalactams):
allergy(pen>ceph>mono)
toxicity(carba(seizures)>ceph(thrombophlebitis)>
pen>mono

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

43

Vancomycin:MechanismofAction
Vancomycin, the crucial drug of last resort, inhibits PG synth
by binding dir ectl y to the D-AlaD-Ala end of the peptide
- forms a cap over the end of the chain; blocks cross-linking

Capped peptides
cannot be cross-linked
Weak
cell walls
cells
die
14022007:09.0010.40
HariPurnomo,ANTIBIOTIKA,FARKIMII.

44

Vancomycin:MechanismofAction

3D model of Vancomycin in
complex with D-AlaD-Ala

note cup-like
shape of Van

Completely surrounds its target peptide, preventing enzymes

from reacting with the end of the peptidoglycan chain
14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

45

Vancom yci n

D-Ala

D-Ala

Vancomycin makes 5 H- bo nds with the

D-AlaD-Ala cap of the PG peptide

14022007:09.0010.40

- Blocks access to tran speptidase enzyme

- You l ive !

HariPurnomo,ANTIBIOTIKA,FARKIMII.

46

VanResistance:DAlaDLactate
Vancomycin-resistant bacteria have peptidoglycan chains that end
in D -Ala D -Lac tat e, instead of the usual D-AlaD-Ala
(A) What genes are necessary to make this change?
(B) How does this confer resistance?
D -Ala D -Ala

D -Ala D -Lac tat

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

e
47

GeneticsofVanResistance
5 gene pr oducts are required to produce Lac-terminal PG
- 2 sensor genes detect Van, turn on other 3 genes
- 2 synthesize the critical D-AlaD-Lactate piece
- 1 destroys the pool of D-AlaD-Ala in the cell (equilibrium)
VanH

VanA

reduction

VanX

1,000 fold lower

affinity for Van

hydrolysis
14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

48

Vancomycin:MechanismofAction

D-AlaD-Ala

cap makes 5 H- bon ds with Vancomycin

D-AlaD-Lac

makes 1 le ss H- bo nd

14022007:09.0010.40

Resistance

HariPurnomo,ANTIBIOTIKA,FARKIMII.

Yo u die
49

GeneticsofVanResistance
Why did penicillin resistance appear in 2 years, but Van resistance
take 30 years to become a major health hazzard?
One answer: geneti c co mp lexity of resistance mechanism
Penicillin resistance requires the activity of one gene pr od uct
(-lactamase enzyme)
- usually 2-4 year lag when only 1 gene is involved
Van resistance takes 5 gen e pr oducts
- apparently delays development of infectious, highly resistant
strains when multiple gene products are involved
14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

50

OvercomingVanResistance
chlorinated
bi-phenyl
substituent

Approach #1: Screening of semi-synthetic analogues of Van

found that hy dr opho bic der ivati ves restore potentcy 100-fold
- Partitions drug to membrane surface, thus altering activity
and availability to target enzymes
14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

51

OvercomingVanResistance
Approach #2: Screening combinatorial libraries for novel small
molecules that cl eave the D-AlaD-Lac depsipeptide
- Look for drugs that can effectively function like an enzyme
Combinatorial library of 300,000 tripeptide derivatives yielded
3 hits , all w/ an N-terminal serine & an intramolecular H-bond
Pharmacophore deduced from computer modelling studies
HO

O
NH2
N

SPr oC 5
14022007:09.0010.40

SProC5 resens iti zed bacteria

with Van-resistance, by cleaving
their D-AlaD-Lac depsipeptide
Chiosis & Boneca, Science 2001

HariPurnomo,ANTIBIOTIKA,FARKIMII.

52

(Vancomycin,teicoplanin[Eur])(Glycopeptides)
ModeofAction:blocktransglycosylation
Resistance:usealalactateratherthanalaalatoend
pentapeptidesidechain
:chromosomal(vanB)andplasmid(vanA)
genes
Uses:Staphylococci,Enterococci,notG

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

53

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

54

a c y lD a la n y lD
a
la
n
in
(R )
3HC

H
N

C
C
O H 3C H

(Z )

R1

NH

C
N
H

OH

H
C

N
H

CO2 C
CH R

HO

H2
C

(R )

CH3 O

Ar
C
H

H
R3

(R )

CombinewithSubstrat

V a n c o m y c in
14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

55

Mekanismekerjayangsejenisdengan
Vancomisin(mengikatDalanilDalanin):
RistocetinA&B,RistomysinA&B,
ActinoidinA&B,AvoparcinA&B,Antibiotik
A35512B

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

56

2.Bacitracin
ModeofAction:blocks~Pandde~Pofbactoprenol
Uses:topicalonlymainlyvs.G+,sousedin
conjunctionw/others
Sideeffects:poorlyabsorbed,renaltoxicity

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

57

Bacitracin

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

58

Mekanismekerjabasitrasin:
Menghambatdeposforilasipiroposfatmembentuk
carrier,sehinggamemblokketersediaanMurNAc
pentapeptida(Sintesatahap2peptidoglikan)

Dindingseltidakterbentuk
14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

59

Cycloserineandphosphonomycin
cycloserine:Dalaanalog,soinhibitsalanineracemase
:neurotoxic,sorarelyused(sometimesforUTI)

Mekanismekerja:
Sikloserinmiripdenganalaninstrukturnya.Adanyasikoserin
menyebabkan/menghalangipembentukanUDPNAcpentapeptida
(tahap1sintesapeptidoglikan)

Dindingseltidakterbentuk
14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

60

HH
O

HH

H
O

H
H

N
C

H
O

L A la n in
H
H

N
N

C
C

O
O

H
H
HH
H
H

HH

O
C N
(E )

S iklo se rin

D A la n in

H
H

H
O
C O
C
(E ) N

SA
ik lo
D
lasneinrin
14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

61

U T P +N A ce tylg lu cosa m in e1 P

SintesisPeptidoglikanada3tahap:
TahapI:
PembentukanUDPNAcMurpentapeptida

p yro ph o sp ha t
U D P G lcN A c

H O 2C
H 2C

PPOE
3 HP

p h o sp h o e n o lp iru va te

U D P G lcN A cpyru va tee n o leth e r

d st...d st

Mekanismekerjaphosphonomycin:
14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

62

H
H 3C

C
O

H O 2C

P O 3H

H 2C

p h o sph o n o m ycin

14022007:09.0010.40

PO 3H

p h o sp h o e n o lp iru vate

H O 2C
H
H 23 C

O
C
O

HariPurnomo,ANTIBIOTIKA,FARKIMII.

H
PO 3H
63

2.Disruptionofcellmembranefunction

Polymyxins

ModeofAction:dissolvephosphatidylethanolamine,a
specializedPLinGmembranes(ours,too)
Uses:toxic,sotopicalonly(ofteninconjunctionwith
bacitracinandneosporin)

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

64

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

65

3.InhibitionofProteinSynthesis
Examples:tetracycline
erytromycin
streptomycin
chloramphenicol

Tetracycline
(aromatic polyketide)

Erythromycin
(macrolide polyketide)
Kanamycin
(aminoglycoside)
14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

66

 Ribosom
Duetodifferencesinribosomes
Eucaryoticcellshave80S(60S+40Ssubunits)
ribosomes.
Procaryoticcellshave70S(50S+30Ssubunits)
ribosomes.
Examples:
Chloramphenicolanderythromycinbindtothe50S
subunit.
Tetracyclinesbindtothe30Ssubunit.

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

67

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

68

ReviewofInitiationofProteinSynthesis
1 3
2 GTP

30S
1
2
Initi atio n
Facto rs

GTP

f-mettRNA
Spectinomyci
n

mRNA
3
GDP + P i
P A

2
1

50S
1
2 GTP

Aminoglycosid
70S
30S
es
Initiation
Initiation
14022007:09.0010.40
HariPurnomo,ANTIBIOTIKA,FARKIMII.
Complex
Complex

69

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

70

ReviewofElongationofProteinSynthesis
Tetr acyc lin
e

P A

Tu GTP

Tu GDP + Pi
Ts

GTP

Tu
Ts

Ts

Fusidi c A cid

P A

GDP
+
G

G GDP + Pi

GDP

Chlo ra mph eni co

l

GT
P

G GTP

P A

P A

Ery th rom yc in
14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

71

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

72

TheActionofAntimicrobialDrugs

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

73
Figure 20.4

1.Aminoglycosides(streptomycin,neomycin,
gentamycin,tobramycin)
ModeofAction:Bindto30Srib,blockinitiationby
preventingattachmentoftRNAfMet
Resistance:alteredP12ribosomalprotein,
aminoglycosidases,alteredpermeability(e.g.
Streptococci)
Uses:Genterics,ofteninsynergywith
cephalosporinsorpenicillins(facilitateentryofthe
aminoglycosides)
14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

74

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

75

2.Tetracycline(doxycycline)

ModeofAction:inhibitsbindingofaatRNAtotheAsite
oftheribosome(30S)
Uses:rickettsia,chlamydia,mycoplasmas
Sideeffects:toxicity,dizziness,ringinginears,
fluorescentteethinnewbornsreplacement
ofnativeflora

Tetracycline
H3C
OH

H3C

CH3
OH

OH
OH

OH

14022007:09.0010.40

Interferewithproteinbiosynthesisatthe
ribosomallevel:bindto30Sribosome
inhibitsubsequentbindingof
aminoacyltransferRNA

C ONH2

HariPurnomo,ANTIBIOTIKA,FARKIMII.

76

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

77

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

78

Tetracycline
H3C
OH

H3C

CH3
OH

OH
OH

14022007:09.0010.40

OH

HariPurnomo,ANTIBIOTIKA,FARKIMII.

C ONH2

79

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

80

DegradationreactioninvolvetheC6hydroxylcleavageoftheCringinalkaline
solution(pH8.5)
stereoorientationoftheC4dimethylaminomoietyessentialforthebioactivity
Epimerizationproduce4epitetracyclineinactive
14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

81

3.Chloramphenicol
ModeofAction:inhibitspeptidyltransferase
reaction(50S)
Resistance:chloramphenicolacetyl
transferase(CAT)
Uses:nolongeradrugofchoice

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

82

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

83

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

84

50SSubunit
Ribosom

SeveralfunctionaldomainsmappedonE.Coli30Sand50Ssubunitsby
thetechniqueofimmuneelectronmicroscopy(CourtesyofDr.H.G.
Wittmann)
14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

85

30SSubunit
Ribosom

SeveralfunctionaldomainsmappedonE.Coli30Sand50Ssubunitsby
thetechniqueofimmuneelectronmicroscopy(CourtesyofDr.H.G.
Wittmann)
14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

86

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

87

4.Macrolides(erythromycin,clarithromycin)
ModeofAction:bindstorRNAandinhibits
translocation(50S)
Resistance:methylationofrRNA
Uses:G+andsomeG
5.Lincomycin/Clindamycin
ModeofAction:sameasmacrolides
Uses:specificuseagainstanaerobes
Bacteroides)doesnotpenetrateCNS

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

88

6.Others:
Nitrofurantoin:inhibits30S,usedvs.
UTI,conc.inurine
Synercid=quinupristin+dalfopristin:
inhibits30S,usedtotreatVREand
VRSAintheUS(Streptograminin
Europe)
Linezolid:inhibits50S,usedtotreat
VREandMRSA
Methenamine:releasesformaldehydein
acidifiedurine,usedtotreatUTI
14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

89

4.Inhibitionofnucleicacidsynthesis
Examples:Rifamycin(Transcription),

Antitbc

Quinolin(DNAreplication)
Nalidixicacid(DNAreplication)
Inhibitionofnucleicacidsynthesis
StopDNAreplication
Manyantiviraldrugsdothis.
Example:AZT
OrstopRNAsynthesis
Example:rifampicin
14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

90

4.DNAinhibitors
1.Quinolones(nalidixicacid)
ModeofAction:inhibitDNAgyrase
Resistance:alteredDNAgyrase,drugexclusion
Uses:notverysoluble,sousefluorinatedQsinstead
(ciprofloxacinandderivatives)vs.UTIandother(mostly)G
infections,butnotPseudomonas

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

91

2.Rifamycin(rifampin)
ModeofAction:blocksRNApolymerase
Resistance:alteredRNApolymerasebsubunit
Uses:withisoniazidtodelayresistancein
Mycobacteria:crossesCNS,sousedfor
meningitis:blocksassemblyofpoxviruses
Sideeffects:excretedinsweatandurine(orange!)
3.Metronidazole
ModeofAction:unknownreactionproductbreaks
DNAstrands
Uses:antiprotozoal(Giardia):vs.anaerobic
bacteria(Bacteriodes,Clostridium)
14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

92

5.Actionasantimetabolites
Examples:Sulfanilamide
Trimetoprim

PABA
Sulfamethoxazole

Trimethoprim
14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

93

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

94

Folic Acid
OH
N

N
H2N

C H2

H
N

CH
C H2

PABA
14022007:09.0010.40

COOH

HariPurnomo,ANTIBIOTIKA,FARKIMII.

C H2
C OOH
95

NH2

NH2

R1

R2

SulfacetamidHCOOH3
SulfadiazineH
R2
R2

SO2NH2

SulfanilamidHH

COOH

R1

Sulf anila mid e Para-aminobenzoic aci

(PABA)
14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

96

AntibacterialAntibiotics
CompetitiveInhibitors
Sulfonamides(Sulfadrugs)
Inhibitfolicacidsynthesis
Broadspectrum

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

97
Figure 5.7

NH2

NH2

SO2NH2

COOH

Sulf anila mid e Para-aminobenzoic aci

(PABA)
14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

98

H 2N

PABA

...........................

OH

...........................

N
6,9 A

O
.
.
.
.
.
.
.

S
NH2

2,4

O ........................
.
.
.
.
.
.
.
.

14022007:09.0010.40

6,7

HO
.
.
.
.

2,3

HariPurnomo,ANTIBIOTIKA,FARKIMII.

O ........................
.
.
.
.
.
.

99

14022007:09.0010.40

HariPurnomo,ANTIBIOTIKA,FARKIMII.

100
Figure 20.13

P teridin

PABA
SMX
E nzim dihidropteroat
sintetase

DHPA

SMX=Sulfametoksazole
TMP=Trimetoprim
PABA=ParaAminoBenzoicAcid
DHPA=DiHydroPteroat
DHFA=DiHydroFolicAcid
THFA=TetraHydroFolicAcid

LG lutam at

DHFA
T im in

TH F A

14022007:09.0010.40

TMP
M etionin,
glisin,adenin,
guanin
HariPurnomo,ANTIBIOTIKA,FARKIMII.

101