Antibiotika: Hari Purnomo

ANTIBIOTIKA
(R )
H H2 H
(R )
3HC N C C O
C
(Z ) C N C
O H 3C H H CH3 O
Hari Purnomo
O H
R1 NH H Ar
C N R3
CO2 C C
N H
HO CH R H (R )
OH
14022007:09.0010.40 HariPurnomo,ANTIBIOTIKA,FARKIMII. 1
Penggolongan :
A. Antibiotika laktam
1. Turunan Penisilin
? a. Sefalosporin kla sik
b. Pra- Sefalosporin
c. Sefamis in
d. Oksasefem
2. Turunaan Sefalosporin
3. Turunan laktam Non Klasik
B. Turunan Amfenikol
C. Turunan Tetrasiklin
D. Turunan Aminoglikosida a. Turunan asam amidinopenisilanat
E. Turunan Makrolida b. Turunan asam penisilanat
c. Karbapenem
F. Turunan Polipeptida d. Oksapenem
G. Turunan Linkosamida e. Turunan laktam Monosiklik
H. Turunan Polien
I. Turunan Ansamisin
J. Turunan Antrasiklin
K. Fosfomisin
Penggolo ngan Berdasarkan Mekanis me
Kerja
TheActionofAntimicrobialDrugs
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
S CH3
R C NH CH CH C basitrasin
CH3
O C N CH COOH
Penicillin nucleus
B-lactam ring
O
S
R C NH CH C C H2 O
O C N C CH2 O C
C
CH3
Cephalosporin nucleus
Cellwallstructure
Gramnegative
Grampositive
Pennicilinbindingprotein(PBP)
Cellwallstructure Gramnegative
Cellwallstructure Grampositive
Pennicilinbindingprotein(PBP)
Spectrumofantimicrobialactivity
NarrowspectrumdrugsaffectonlyGram
positivecellsoronlyGramnegativecells.
BroadspectrumdrugsaffectbothGrampositive
andGramnegativecells.
Thenormalfloraisaffected,too.
Fig.131
AntibioticTarget1:CellWall
Cell wall is pep tido gl ycan , a repeating polymer of di-
saccharide,
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
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
Bakteri..Dindingselbakteri..Peptidoglikan
SintesisPeptidoglikanada3tahap:
TahapI:PembentukanUDPNAcMurpentapeptida
TahapII:Pembentukanakseptordekapeptidamid
TahapIII:Pembentukanpeptidoglikan(salahsatu
bahanbakuDAlanilDAlanin)
(Penisilin,sefalosporinbekerjapadatahapini)
Penicillins and Cephalospo
O
S CH3
R C NH CH CH C
CH3
O C N CH COOH
Penicillin nucleus
B-lactam ring
O
S
R C NH CH C C H2 O
O C N C CH2 O C
C
CH3
Cephalosporin nucleus
Peni c i l l i ns
O
S CH3
R C NH CH CH C
CH3
O C N CH COOH
B-lactam ring
Common nucleus
.History
AlexanderFleming(1928)
InEngland,noticedthatS.aureusdidnotgrow
aroundacolonyofmoldonagar
ThemoldwasPenicilliumnotatum.
Heisolatedtheinhibitorysubstance.Calledit
penicillin.
Penicillinwasunstable.
FloreyandChain(1940)
InEngland
Resumedstudyofpenicillin
Isolatedandpurifiedpenicillin
USAbecameinvolved
PenicillinusedduringWWII
Penicillinisanantibiotic.
Antibioticisfromantibiosis,meaningagainst
life.
antibioticAsubstancethatisproducedbyone
microorganism(abacteriumorfungus)thatkills
orinhibitsthegrowthofanothermicroorganism.
Majorproducersofantibioticsdiscovered
throughouttheyears:
Molds
Penicillium
Cephalosporium
Bacteria
Streptomyces
Bacillus
(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
Penicillins
O
S CH3
Penicillin G CH2 C NH CH C H C
CH3
O C N CH COOH
Penicill in V O CH2 Common nucleus
Ampicillin CH Common nucleus

NH2
CH2
R=
Benzil penisilin ( Penisilin G )
OCH2
R=
Fenoksimetilpenisilin
( Penisilin V )
NH2
R = CH
A m p is ilin
NH2
R= CH
Amoksisilin
HO
OCH3
R= Metisilin
OCH3
Cl
CH
R=
HN
O Kloksasilin
O O
H 3C OH H OH
H H
(S ) (S )
C C
H 3C H
N N "H
S H
H
O O
(R )
H H
(R )
H (S ) H
N' N'
R O R O

Penisilin
14022007:09.0010.40 HariPurnomo,ANTIBIOTIKA,FARKIMII.
DAlanilDAlanin
29
StabilitascincinLactam
DegradasidenganLactamase
DegradasidenganLactamase
S
S
N
HN
H O C H O
H C
X O OH
N X O OH
N
H
H
E nzim
E nzim
Resistance:lactamaseEnzymes
Bacteria produce enzymes to hydr olyze the -la ctam r ing

before
drugs can reach inner membrane
14022007:09.0010.40
where PG synthesis occcurs
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
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
ResistenLactamase
Lesstolerancetothesterichindrancenearthesidechainofamidabond.
Attacheddirectlytothesidechaincarbonylandbothorthopositionaresustitutedby
methoxyresistant
MovementofoneoftheOCH3toparaposition,puttingmethylenbetweenthearomatic
ring6APAsensitif
ResistanttoenzymedegradationbasedondifferentialSterichindrance
Stabilitasterhadapasam
Stabilitasterhadapasam
CH3
O C O
H O
H H OH
H 2C (S )
(S )
C
N H
S N "H
H H
O
(R ) O
H
H (S ) (R ) H
N' H
N'
DAlanilDAlanin
R O
Cephalo spori ns
R O
(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
(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
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
14022007:09.0010.40 cells die
3D model of Vancomycin in note cup-like

complex with D-AlaD-Ala shape of Van
Completely surrounds its target peptide, preventing enzymes

from reacting with the end of the peptidoglycan chain
Vancom yci n
D-Ala D-Ala
Vancomycin makes 5 H- bo nds with the
D-AlaD-Ala cap of the PG peptide
- Blocks access to tran speptidase enzyme

- You l ive !
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 e
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

hydrolysis affinity for Van
D-AlaD-Ala cap makes 5 H- bon ds with Vancomycin

D-AlaD-Lac makes 1 le ss H- bo nd Resistance Yo u die
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
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
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 SProC5 resens iti zed bacteria
O
NH2
with Van-resistance, by cleaving
N their D-AlaD-Lac depsipeptide
SPr oC 5 Chiosis & Boneca, Science 2001
(Vancomycin,teicoplanin[Eur])(Glycopeptides)
ModeofAction:blocktransglycosylation
Resistance:usealalactateratherthanalaalatoend
pentapeptidesidechain
:chromosomal(vanB)andplasmid(vanA)
genes
Uses:Staphylococci,Enterococci,notG
a c y lD a la n y lD
(R )
a la n in
H H2 H
(R )
3HC N C C O
C
(Z ) C N C
O H 3C H H CH3 O
O H
R1 NH H Ar
C N R3
CO2 C C
N H
HO CH R H (R )
OH CombinewithSubstrat
V a n c o m y c in
Mekanismekerjayangsejenisdengan
Vancomisin(mengikatDalanilDalanin):
RistocetinA&B,RistomysinA&B,
ActinoidinA&B,AvoparcinA&B,Antibiotik
A35512B
2.Bacitracin
ModeofAction:blocks~Pandde~Pofbactoprenol
Uses:topicalonlymainlyvs.G+,sousedin
conjunctionw/others
Sideeffects:poorlyabsorbed,renaltoxicity
Bacitracin
Mekanismekerjabasitrasin:
Menghambatdeposforilasipiroposfatmembentuk
carrier,sehinggamemblokketersediaanMurNAc
pentapeptida(Sintesatahap2peptidoglikan)
Dindingseltidakterbentuk
Cycloserineandphosphonomycin
cycloserine:Dalaanalog,soinhibitsalanineracemase
:neurotoxic,sorarelyused(sometimesforUTI)
Mekanismekerja:
Sikloserinmiripdenganalaninstrukturnya.Adanyasikoserin
menyebabkan/menghalangipembentukanUDPNAcpentapeptida
(tahap1sintesapeptidoglikan)
Dindingseltidakterbentuk
H H H H H H
H H
N C H N C H H C N H
HH H HH O HH H
C O C N C
O O (E ) O
O
D A la n in S iklo se rin L A la n in
H
H H
H
H
H
N
N C
C H
H
HH
H H OH
C O
C
(E ) N
O
O
SA
D ik lo
lasneinrin
SintesisPeptidoglikanada3tahap: U T P +N A ce tylg lu cosa m in e1 P
TahapI:
PembentukanUDPNAcMurpentapeptida
p yro ph o sp ha t
U D P G lcN A c
H O 2C
C O
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:
H H O 2C
H
C C C O
H 3C P O 3H H 2C PO 3H
O
p h o sph o n o m ycin p h o sp h o e n o lp iru vate
H O 2C
H
H
C O
C
H 23 C PO 3H
O
2.Disruptionofcellmembranefunction
Polymyxins
ModeofAction:dissolvephosphatidylethanolamine,a
specializedPLinGmembranes(ours,too)
Uses:toxic,sotopicalonly(ofteninconjunctionwith
bacitracinandneosporin)
3.InhibitionofProteinSynthesis
Examples:tetracycline
erytromycin
streptomycin Tetracycline
(aromatic polyketide)
chloramphenicol
Erythromycin
(macrolide polyketide)
Kanamycin
(aminoglycoside)
Ribosom
Duetodifferencesinribosomes
Eucaryoticcellshave80S(60S+40Ssubunits)
ribosomes.
Procaryoticcellshave70S(50S+30Ssubunits)
ribosomes.
Examples:
Chloramphenicolanderythromycinbindtothe50S
subunit.
Tetracyclinesbindtothe30Ssubunit.
ReviewofInitiationofProteinSynthesis
1 3
30S 2 GTP
1 2 3 GTP
Initi atio n
Facto rs f-met-
mRNA tRNA
Spectinomyci
n
3
GDP + P i
2
50S
P A
1 1
2 GTP
70S Aminoglycosid
30S
Initiation es
14022007:09.0010.40
Initiation
Complex Complex
ReviewofElongationofProteinSynthesis
Tetr acyc lin
P A P A
e
Tu GTP Tu GDP + Pi
GTP Ts
Ts Tu
Ts GDP
Chlo ra mph eni co
l
GDP
Fusidi c A cid +
GT
G
P
G GDP + Pi
G GTP
P A P A
Ery th rom yc in
TheActionofAntimicrobialDrugs
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)
2.Tetracycline(doxycycline)
ModeofAction:inhibitsbindingofaatRNAtotheAsite
oftheribosome(30S)
Uses:rickettsia,chlamydia,mycoplasmas
Sideeffects:toxicity,dizziness,ringinginears,
fluorescentteethinnewbornsreplacement
ofnativeflora
Tetracycline
Interferewithproteinbiosynthesisatthe
H3C ribosomallevel:bindto30Sribosome
N CH3
H3C OH
inhibitsubsequentbindingof
OH
aminoacyltransferRNA
OH C ONH2
OH O OH O
Tetracycline
H3C
N CH3
H3C OH
OH
OH C ONH2
OH O OH O
DegradationreactioninvolvetheC6hydroxylcleavageoftheCringinalkaline
solution(pH8.5)
stereoorientationoftheC4dimethylaminomoietyessentialforthebioactivity
Epimerizationproduce4epitetracyclineinactive
3.Chloramphenicol
ModeofAction:inhibitspeptidyltransferase
reaction(50S)
Resistance:chloramphenicolacetyl
transferase(CAT)
Uses:nolongeradrugofchoice
50SSubunit
Ribosom
SeveralfunctionaldomainsmappedonE.Coli30Sand50Ssubunitsby
thetechniqueofimmuneelectronmicroscopy(CourtesyofDr.H.G.
Wittmann)
30SSubunit
Ribosom
SeveralfunctionaldomainsmappedonE.Coli30Sand50Ssubunitsby
thetechniqueofimmuneelectronmicroscopy(CourtesyofDr.H.G.
Wittmann)
4.Macrolides(erythromycin,clarithromycin)
ModeofAction:bindstorRNAandinhibits
translocation(50S)
Resistance:methylationofrRNA
Uses:G+andsomeG
5.Lincomycin/Clindamycin
ModeofAction:sameasmacrolides
Uses:specificuseagainstanaerobes
Bacteroides)doesnotpenetrateCNS
6.Others:
Nitrofurantoin:inhibits30S,usedvs.
UTI,conc.inurine
Synercid=quinupristin+dalfopristin:
inhibits30S,usedtotreatVREand
VRSAintheUS(Streptograminin
Europe)
Linezolid:inhibits50S,usedtotreat
VREandMRSA
Methenamine:releasesformaldehydein
acidifiedurine,usedtotreatUTI
4.Inhibitionofnucleicacidsynthesis
Examples:Rifamycin(Transcription), Antitbc
Quinolin(DNAreplication)
Nalidixicacid(DNAreplication)
Inhibitionofnucleicacidsynthesis
StopDNAreplication
Manyantiviraldrugsdothis.
Example:AZT
OrstopRNAsynthesis
Example:rifampicin
4.DNAinhibitors
1.Quinolones(nalidixicacid)
ModeofAction:inhibitDNAgyrase
Resistance:alteredDNAgyrase,drugexclusion
Uses:notverysoluble,sousefluorinatedQsinstead
(ciprofloxacinandderivatives)vs.UTIandother(mostly)G
infections,butnotPseudomonas
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)
5.Actionasantimetabolites
Examples:Sulfanilamide
Trimetoprim
PABA
Sulfamethoxazole
Trimethoprim
Folic Acid
OH H O COOH
N H
N C H2 N C N CH
N N C H2
H2N
C H2
PABA C OOH
NH2 NH2
R1 R2
SulfacetamidHCOOH3
N
SulfadiazineH N
R2
R2 SulfanilamidHH
SO2NH2 COOH
R1
Sulf anila mid e Para-aminobenzoic aci

(PABA)
AntibacterialAntibiotics
CompetitiveInhibitors
Sulfonamides(Sulfadrugs)
Inhibitfolicacidsynthesis
Broadspectrum
Figure 5.7
NH2 NH2
SO2NH2 COOH
Sulf anila mid e Para-aminobenzoic aci

(PABA)
H 2N

PABA

O C OH
H
H H ...........................
H ...........................
N N
6,9 A 6,7
S HO C O ........................
O O ........................ .
. . .
. .
. NH2 .
. .
. .
. 2,3 .
. .
. . .
. 2,4 . .
. .
.
Figure 20.13
P teridin PABA
SMX
SMX=Sulfametoksazole
TMP=Trimetoprim
E nzim dihidropteroat PABA=ParaAminoBenzoicAcid
sintetase DHPA=DiHydroPteroat
DHFA=DiHydroFolicAcid
DHPA THFA=TetraHydroFolicAcid
LG lutam at
DHFA
TMP
T im in TH F A M etionin,
glisin,adenin,
guanin

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ANTIBIOTIKA

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

-lactam antibiotics interfere with cell wall biosynthesis of

TPase cuts off #5

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

Penicill in V O CH2 Common nucleus

Ampicillin CH Common nucleus

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

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

(cell wall enz.)

3D model of Vancomycin in note cup-like

Completely surrounds its target peptide, preventing enzymes

- Blocks access to tran speptidase enzyme

D -Ala D -Lac tat e

VanX 1,000 fold lower

D-AlaD-Ala cap makes 5 H- bon ds with Vancomycin

One answer: geneti c co mp lexity of resistance mechanism

Penicillin resistance requires the activity of one gene pr od uct

Van resistance takes 5 gen e pr oducts

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

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

p h o sph o n o m ycin p h o sp h o e n o lp iru vate

Sulf anila mid e Para-aminobenzoic aci

Sulf anila mid e Para-aminobenzoic aci

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