protein synth in hib ge recke 2408

7/31/2019 Protein Synth in Hib Ge Recke 2408

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Inhibitors of Bacterial Protein SynthesisInhibitors of Bacterial Protein Synthesis

Pharmacology II February 4, 2008Pharmacology II February 4, 2008

Dr. Don Gerecke, Room 410, EOHSIDr. Don Gerecke, Room 410, EOHSI732732--445445--02330233 [email protected]@eohsi.rutgers.edu

Reference: Basic & Clinical Pharmacology, Bertram G.Reference: Basic & Clinical Pharmacology, Bertram G. KatzungKatzung,,

Chapter 44, pp. 774Chapter 44, pp. 774--783; Chapter 47, pp. 803783; Chapter 47, pp. 803--819.819.


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Sites of Action of Antibiotics

peptolidespeptolides

metronidazolemetronidazole

DNA synthesisDNA synthesis

ProteinProtein synthsynth

otherotherQuinupristinQuinupristinDalfopristinDalfopristinLinezolidLinezolidstreptograminsstreptogramins


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Many antibiotics target bacterialMany antibiotics target bacterialribosome which differs structurallyribosome which differs structurally

from mammalianfrom mammalian cytoplasmiccytoplasmicribosomesribosomes..

However mitochondrialHowever mitochondrial ribosomesribosomes

are more similar and high dosesare more similar and high dosesofoftetracyclinestetracyclines

oror chloramphenicolchloramphenicol

can be toxic at this site.can be toxic at this site.

OVERVIEWOVERVIEW


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Bacterial ProteinBacterial ProteinSynthesisSynthesis

DNADNA gyrasegyrase

RNA polymeraseRNA polymerase

30S initiation complex30S initiation complex


PeptidylPeptidyl

transferasetransferase

Enzyme to relax DNA and allow RNAEnzyme to relax DNA and allow RNApolymerase to produce RNApolymerase to produce RNA

Makes the mRNAMakes the mRNA

30S comes together with mRNA and30S comes together with mRNA and formylformylmethioninemethionine

andand tRNAtRNA

to form this complexto form this complex

50S ribosomal unit joins to make 70s complex50S ribosomal unit joins to make 70s complexand allow amino acids to be addedand allow amino acids to be added

The enzyme which catalyzes the peptide bondThe enzyme which catalyzes the peptide bond

formations of the growing peptide chainformations of the growing peptide chain

MammalianMammaliansubunits aresubunits are40S, 60S, 80S40S, 60S, 80S


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Bacterial ProteinBacterial ProteinSynthesisSynthesis

DNADNA gyrasegyrase

RNA polymeraseRNA polymerase



PeptidylPeptidyl


Enzyme to relax DNA and allow RNAEnzyme to relax DNA and allow RNApolymerase to produce RNApolymerase to produce RNA

Makes the mRNAMakes the mRNA

30S comes together with mRNA and30S comes together with mRNA and formylformylmethioninemethionine

andand tRNAtRNA

to form this complexto form this complex

50S ribosomal unit joins to make 70s complex50S ribosomal unit joins to make 70s complexand allow amino acids to be addedand allow amino acids to be added

The enzyme which catalyzes the peptide bondThe enzyme which catalyzes the peptide bond

formations of the growing peptide chainformations of the growing peptide chain

Forms stable complexForms stable complex

with polymerasewith polymerase

Inhibits DNA synthesisInhibits DNA synthesis

Binds 30S unit and interferes withBinds 30S unit and interferes withtRNAtRNA

binding to mRNA complexbinding to mRNA complex

Binds 50S unit in a way that interferesBinds 50S unit in a way that interfereswithwith peptidylpeptidyl


Binds 30S unit and interferes withBinds 30S unit and interferes with70S initiation complex formation70S initiation complex formation

Binds 50S in a way that interferes withBinds 50S in a way that interferes withpeptide bond formationspeptide bond formations

((MacrolideMacrolide))


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Steps in BacterialSteps in BacterialProtein SynthesisProtein Synthesis

1)1)

ChargedCharged tRNAtRNA

carries amino acidcarries amino acid

2)2)

Binds to acceptor site on 50S subunitBinds to acceptor site on 50S subunit

3)3)

PeptidylPeptidyl

tRNAtRNA

already on donor sit on 50S subunitalready on donor sit on 50S subunit

4)4)

PeptidylPeptidyl


catalyzes donation of growing peptide chain tocatalyzes donation of growing peptide chain to aminoacylaminoacyl

tRNAtRNA

5)5)

tRNAtRNA

at donor site released (uncharged)at donor site released (uncharged)

6)6) Growing chain at acceptor site moves to donor site and process sGrowing chain at acceptor site moves to donor site and process starts againtarts again


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BlocksBlocks binding ofbinding ofaminoacylaminoacyl

moiety of the chargedmoiety of the charged tRNAtRNA

moleculemolecule

to the acceptor site of ribosomal mRNA complex.to the acceptor site of ribosomal mRNA complex. tRNAtRNA

bindingbinding

to mRNA unaffected. Canto mRNA unaffected. Cant transfer peptide from donor and proteint transfer peptide from donor and proteinsynthesis stops.synthesis stops.

Prevent translocation ofPrevent translocation ofpeptidylpeptidyl

tRNAtRNA

from acceptor site to donor site. Stallsfrom acceptor site to donor site. Stallssystem, cansystem, cant move newt move new tRNAtRNA

to acceptorto acceptor

Binds 30S subunit and directly blocksBinds 30S subunit and directly blocksbinding of amino acidbinding of amino acid--chargedcharged tRNAtRNA

to the acceptor site.to the acceptor site.

SITES OF ACTIONSITES OF ACTION

1)1) ChloramphenicolChloramphenicol

2)2) MacrolidesMacrolides,, ClindamycinClindamycin, type B, type BStreptograminsStreptogramins,, TelithromycinTelithromycin

3)3) TetracyclinesTetracyclines


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TetracyclinesTetracyclines

Crystalline,Crystalline,

amphotericamphoteric

substances of low solubilitysubstances of low solubility

Structurally are 4Structurally are 4--ringed (TETRA) with amino groups, methyl groups andringed (TETRA) with amino groups, methyl groups and sidechainssidechains..

They readily penetrate microbialThey readily penetrate microbial

membranes (passive diffusion) ormembranes (passive diffusion) orthru an energythru an energy--dependent transportdependent transportsystem specific to bacterial innersystem specific to bacterial innercytoplasmiccytoplasmic

membrane.membrane.

NonNon--resistant strains concentrate theresistant strains concentrate thetetracyclinestetracyclines

intracellularlyintracellularly..

I hibit f P t i S th iI hibit f P t i S th i


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Selectively toxic for bacteria becauseSelectively toxic for bacteria becausemammalian cells lack the activemammalian cells lack the activetransport system that transports themtransport system that transports theminto bacteria.into bacteria.

Reversibly binds to the 30S ribosomalReversibly binds to the 30S ribosomalunit and inhibits the binding ofunit and inhibits the binding ofaminoaminoacylacyl--tRNAtRNA

to the mRNAto the mRNA--ribosomeribosome

complex at the acceptor site on thecomplex at the acceptor site on the50S subunit.50S subunit.

TetracyclinesTetracyclines

Inhibitors of Protein SynthesisInhibitors of Protein Synthesis


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PenicillinsPenicillins

were excellent forwere excellent for StaphylococciStaphylococci

andand StreptococciStreptococci, but not TB Salmon Waxman, but not TB Salmon Waxman

looked at soil microbes and discovered andlooked at soil microbes and discovered andisolated Streptomycin.isolated Streptomycin.

Were extensively used for aerobic gramWere extensively used for aerobic gram--negativenegative

bacilli.bacilli.

Because of serious potential for toxicity, mostlyBecause of serious potential for toxicity, mostlynot used.not used.


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Basic structure is two or more amino sugars linked toBasic structure is two or more amino sugars linked to centralhexosecentralhexose

nucleus.nucleus.

StreptomycesStreptomycesderived arederived are mycinmycin::MicromonosporaMicromonosporaderived arederived are --micinmicin..

Have eitherHave either streptidinestreptidine

oror deoxystreptaminedeoxystreptamine

(ring II in right figure) attached via(ring II in right figure) attached via glycosidicglycosidiclinkages to amino sugars.linkages to amino sugars.

Each drug characterized byEach drug characterized bythe number and kind ofthe number and kind of

amino sugars.amino sugars.

AminoglycosidesAminoglycosides


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MECHANISM OF ACTIONMECHANISM OF ACTION

Susceptible gramSusceptible gram--negneg

organisms alloworganisms allow

entry thruentry thru porinporin

channels in outer membrane.channels in outer membrane.

Also requires oxygenAlso requires oxygen--dependent transportdependent transport

system.system.

Then irreversibly binds to 30S ribosomalThen irreversibly binds to 30S ribosomalsubunit prior to ribosomal formation.subunit prior to ribosomal formation.

End results:End results:

1)1)

Causes 30S to misread genetic code.Causes 30S to misread genetic code.

2)2)

PolysomesPolysomes

(groups of(groups ofribosomesribosomes))

become depleted.become depleted.

All are bactericidal.All are bactericidal.


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are antibacterialare antibacterial

in two ways:in two ways:

1)1)

Disrupt bacterial membrane integrity.Disrupt bacterial membrane integrity.

All the positive charges allow them to bind the negativeAll the positive charges allow them to bind the negativebacterial cell membrane, disrupting it.bacterial cell membrane, disrupting it.

Also bind phospholipids in mammalian renal proximalAlso bind phospholipids in mammalian renal proximal

tubular cells resulting in some toxicity.tubular cells resulting in some toxicity.

Most other mammalian cells hydrophobic, so no problem.Most other mammalian cells hydrophobic, so no problem.


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Once inside they bind to 30SOnce inside they bind to 30Sribosomal unit and disrupt theribosomal unit and disrupt the

initiation of protein synthesis.initiation of protein synthesis.

PostantibioticPostantibiotic

effecteffect ContinueContinue

to suppress bacterial reto suppress bacterial re--growthgrowtheven after antibiotic removed.even after antibiotic removed.

Probably due to initial disruptionProbably due to initial disruptionofofribosomesribosomes; it may take time; it may take timeto synthesize newto synthesize new ribosomesribosomes..

2) Interfere with protein synthesis2) Interfere with protein synthesis

i l id ffi l l ff i i i


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particularly effective against gramparticularly effective against gram--negativenegative

bacteriabacteria

Positive charge allows membrane disruption and easy access thruPositive charge allows membrane disruption and easy access thruporinsporins

Two Phases:Two Phases:

1)1) CytosolCytosol

must have negative electron potentialmust have negative electron potential

2) Transport is oxygen dependent2) Transport is oxygen dependent

Process is inhibited at low pHProcess is inhibited at low pH

Inhibited at low oxygen tensionInhibited at low oxygen tension

This also explains whyThis also explains why

aminoglycosidesaminoglycosides

areare

ineffective to anaerobesineffective to anaerobes

Bacterial abscesses haveBacterial abscesses havelow pH and low oxygenlow pH and low oxygen

tension, so to overcometension, so to overcomeit, coit, co--administer with aadminister with abetabeta--lactamlactam

to disruptto disrupt

cell membrane and getcell membrane and getpenetration.penetration.

A i l idA i l id ff i h iff t t i th i


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AminoglycosideAminoglycoside

effects on protein synthesiseffects on protein synthesis

Block of initiationBlock of initiationcomplexcomplex

Miscoding ofMiscoding ofamino acidsamino acids

Block ofBlock of

translocationtranslocationon mRNAon mRNA

They interfere in proteinThey interfere in proteinsynthesis in 3 wayssynthesis in 3 ways

Block formation of 70SBlock formation of 70Sinitiation complexinitiation complex

Cause the mRNA to beCause the mRNA to bemisread and make themisread and make thewrong amino acidwrong amino acid

Blocks the ribosomeBlocks the ribosomefrom moving downfrom moving down

the mRNA and getthe mRNA and gettruncated polypeptidetruncated polypeptide


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AminoglycosidesMechanism of Resistance

Alteration in aminoglycoside uptake decreased penetration of aminoglycoside

Synthesis of aminoglycoside-modifying

enzymes

plasmid-mediated; modifies the structure of the

aminoglycoside which leads to poor binding toribosomes

Alteration in ribosomal binding sites


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OnceOnce--DailyDaily AminoglycosideAminoglycoside

DosingDosing

1)1)

ConcentrationConcentration--dependent killingdependent killing

At increasing concentration, kill more bacteria at a more rapidAt increasing concentration, kill more bacteria at a more rapid raterate

In opposition to timeIn opposition to time--dependent killingdependent killingamount of time above minimumamount of time above minimuminhibitory concentration as betainhibitory concentration as beta--lactamslactams..

Antibacterial activity beyond measurable drug..maybe several houAntibacterial activity beyond measurable drug..maybe several hoursrs

Toxicity is both time and concentration dependent.Toxicity is both time and concentration dependent.

Toxicity doesnToxicity doesnt occur until a certain threshold concentration achieved.t occur until a certain threshold concentration achieved.

Once concentration achieved, time above this threshold becomes cOnce concentration achieved, time above this threshold becomes critical.ritical.

So single high dose more efficacious and less toxic than multiplSo single high dose more efficacious and less toxic than multiple smaller doses.e smaller doses.

2)2) PostantibioticPostantibiotic

effectseffects

I hibit f P t i S th iInhibitors of Protein S nthesis


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MacrolidesMacrolides

LargeLarge lactonelactone

ring with sugars attachedring with sugars attached

Binds 50S ribosomal subunit and interferes with peptide bond forBinds 50S ribosomal subunit and interferes with peptide bond formationmation

of growing polypeptide chain:of growing polypeptide chain:

DoesnDoesnt get into mammalian mitochondria,t get into mammalian mitochondria,so less toxic thanso less toxic than chloramphenicolchloramphenicol..

Thus, bacterial peptides truncatedThus, bacterial peptides truncatedand nonand non--functional.functional.


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Macrolides

Mechanism of Action

Inhibits protein synthesis by reversibly bindingto the 50S ribosomal subunit

Suppression of RNA-dependent protein synthesisMacrolides typically display bacteriostatic

activity, but may be bactericidal when present

at high concentrations against very susceptibleorganisms

Time-dependent activity


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Macrolides

Mechanisms of Resistance

Active efflux (accounts for 80% in US) mefgene encodes

for an efflux pump which pumps the macrolide out of the

cell away from the ribosome

Altered target sites (primary resistance mechanism in

Europe) encoded by the erm gene which alters the

macrolide binding site on the ribosome by encoding

dimethyltransferase which adds dimethyl group to

ribosomal binding site

Cross-resistance occurs between all macrolides

I hibit f P t i S th iI hibit f P t i S th i


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ChloramphenicolChloramphenicol

Potent inhibitor of microbial protein synthesisPotent inhibitor of microbial protein synthesis

Binds reversibly to 50S subunit of ribosome (doesnBinds reversibly to 50S subunit of ribosome (doesnt bind 80st bind 80s

mammalian form, but yes binds 70s complex in mitochondria)mammalian form, but yes binds 70s complex in mitochondria)

It interferes with action ofIt interferes with action ofpeptidylpeptidyl


((transacetylasetransacetylase))

First isolated fromFirst isolated from StreptomycesStreptomyces 19471947

Nitrobenzene derivative:Nitrobenzene derivative:First completely synthetic antibiotic produced commerciallyFirst completely synthetic antibiotic produced commercially


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Clindamycin is a

semisynthetic derivative

of lincomycin which wasisolated from Streptomyces

lincolnesis in 1962.


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Clindamycin

Mechanism of Action

Inhibits protein synthesis by bindingexclusively to the 50S ribosomal subunit

Binds in close proximity to macrolides competitive inhibition

Clindamycin typically displays bacteriostatic

activity, but may be bactericidal when presentat high concentrations against very susceptible

organisms


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Clindamycin

Mechanisms of Resistance

Altered target sites encoded by the erm genewhich alters the clindamycin binding site on the

ribosome

Active efflux mefgene encodes for an efflux

pump which pumps the macrolide out of the cell

but NOT clindamycin


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Streptogramins Synercid is the first available agent which

received FDA approval in September 1999

Developed in response to need for agents with

activity against resistant gram-positives (VRE) Synercid is a combination of two semi-

synthetic pristinamycin derivatives in a 30:70w/w ratio:

Quinupristin:Dalfopristin


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Synercid

Structure


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Synercid

Mechanism of Action

Each agent acts on 50S ribosomal subunitsto inhibit early and late stages of proteinsynthesis

Bacteriostatic (cidal against some bacteria)

Mechanism of Resistance Alterations in ribosomal binding sites

Enzymatic inactivation

QuinupristinQuinupristin blocksblocks Mechanisms ofMechanisms of


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LinezolidLinezolid

QuinupristinQuinupristin

DalfopristinDalfopristin

QuinupristinQuinupristin

blocksblocks

aminoacylaminoacyl--tRNAtRNAcomplexes fromcomplexes from

binding to thebinding to theribosomeribosome

DalfopristinDalfopristin

inhibitsinhibits

peptide bondpeptide bondformation andformation andpromotes bindingpromotes binding

ofofquinupristinquinupristin

LinezolidLinezolid

bindsbinds

50S subunit50S subunitvery early invery early incell cyclecell cycle

Mechanisms ofMechanisms ofActionAction


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MulticyclicMulticyclic

compoundscompounds

sometimes with fused ringssometimes with fused rings

Oxazolidinones


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Linezolid

Mechanism of Action

Binds to the 50S ribosomal subunit near to surfaceinterface of 30S subunit causes inhibition of 70S

initiation complex which inhibits protein synthesis

Bacteriostatic (bactericidal against some bacteria)

Mechanism of Resistance

Alterations in ribosomal binding sites (RARE) Cross-resistance with other protein synthesis

inhibitors is unlikely, cause early in cell cycle

when ribosome still being made


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Miscellaneous AntibioticsMiscellaneous Antibiotics

FLUOROQUINOLONESFLUOROQUINOLONES


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Novel group of synthetic antibioticsNovel group of synthetic antibioticsdeveloped in response to growingdeveloped in response to growing

resistance.resistance.

Agents available today are structuralAgents available today are structuralderivatives ofderivatives of nalidixicnalidixic acid.acid.

TheThe fluorinatedfluorinatedquinolonesquinolones ((FQsFQs))

represent major therapeutic advance:represent major therapeutic advance:

Broad spectrum of activityBroad spectrum of activity

Improved PK propertiesImproved PK properties

excellent bioavailability, tissueexcellent bioavailability, tissuepenetration, prolonged halfpenetration, prolonged half--liveslives

Overall safetyOverall safety

Disadvantages: resistance, expenseDisadvantages: resistance, expense

FLUOROQUINOLONESFLUOROQUINOLONES

SulfanilamideSulfanilamide

FluoroquinolonesFluoroquinolones Synthetic fluorinated analogs ofSynthetic fluorinated analogs ofnalidixicnalidixic acidacidFluorinateFluorinate quinolonequinolone ring to get namering to get name


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MultiMulti--cyclic with fused rings..all havecyclic with fused rings..all have quinolonequinolone

(left) and(left) and naphthyridonenaphthyridone

(right) rings(right) rings

FluorinateFluorinate quinolonequinolone

ring to get namering to get name


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Fluoroquinolones

Mechanism of Action

Unique mechanism of action

Inhibit bacterial topoisomerases which are necessary

for DNA synthesis

DNA gyrase (Topo II) removes excess positive supercoiling

in the DNA helix

Primary target in gram-negative bacteria

Topoisomerase IV essential for separation of interlinked

daughter DNA molecules

Primary target for many gram-positive bacteria

FQs display concentration-dependent bactericidal

activity

Mechanism of Action ofMechanism of Action ofFluoroquinolonesFluoroquinolones


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Enter thruEnter thru porinsporins

and by passiveand by passive

diffusion into cell.diffusion into cell.

Inhibits DNAInhibits DNA gyrasegyrase

((TopoTopo

II)II)

preventing relaxation ofpreventing relaxation ofsupercoiledsupercoiledDNA that is required for normalDNA that is required for normaltranscription and replicationtranscription and replication

Also inhibitsAlso inhibits topoisomerasetopoisomerase

IVIV

which is required for separationwhich is required for separationof replicated chromosomal DNAof replicated chromosomal DNAinto daughter cells during divisioninto daughter cells during division

SulfonamidesSulfonamides


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SulfonamidesSulfonamides

All structural analogs ofAll structural analogs ofpp--aminobenzoicaminobenzoicacid (PABA)acid (PABA)

Competitively inhibit incorporation of PABACompetitively inhibit incorporation of PABAinto folic acidinto folic acid

More soluble at alkaline, so oftenMore soluble at alkaline, so oftensodium salts formulation.sodium salts formulation.

By competitively inhibitingBy competitively inhibiting dihydropteroatedihydropteroatesynthasesynthase

(reversibly) so are(reversibly) so are bacteriostaticbacteriostatic,,

inhibiting cell growth, and not bactericidal.inhibiting cell growth, and not bactericidal.

Folic acid is necessary for bacterialFolic acid is necessary for bacterialreplication without it cells wonreplication without it cells wontt


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Humans canHumans cant synthesize folic acidt synthesize folic acidand get it through diet, so sulfonamidesand get it through diet, so sulfonamidesspecific to microbes, but humans needspecific to microbes, but humans needfinalfinal tetrahydrofolatetetrahydrofolate

as coenzyme.as coenzyme.

replication, without it cells wonreplication, without it cells wonttgrow and divide.grow and divide.

SulfanilamideSulfanilamide


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Resistance due to:Resistance due to:

1)1)

Decreased bacterial permeability to the drug.Decreased bacterial permeability to the drug.

2)2)

Increased PABA synthesis to dilute the competitor.Increased PABA synthesis to dilute the competitor.

3)3) Structural changes in folic acid synthesizing enzyme.Structural changes in folic acid synthesizing enzyme.

TrimethoprimTrimethoprim


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Structural analogue ofStructural analogue ofdihydrofolicdihydrofolic

acidacid

InhibitsInhibits dihydrofolatedihydrofolate

reductasereductase

needed to turnneeded to turn dihydrofolicdihydrofolic

acidacid

intointo tetrahydrofolictetrahydrofolic

acidacid

Resistance due to:Resistance due to:

1) Alterations in1) Alterations in dihydrofolatedihydrofolate

reductasereductase

2) Impermeability to the drug2) Impermeability to the drug

3) Overproduction of3) Overproduction ofdihydrofolatedihydrofolate

reductasereductase

Often administered withOften administered with sulfamethoxazolesulfamethoxazoleBecause they have similar halfBecause they have similar half--lives.lives.

PolymyxinsPolymyxins


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FromFrom BacillusBacilluspolymyxapolymyxa, assembled from, assembled from diaminodiamino

butyric acid units (DAB)butyric acid units (DAB)

Get membrane distortion, loss of selectiveGet membrane distortion, loss of selectivepermeability, leakage of metabolites, andpermeability, leakage of metabolites, andinhibition of cellular processesinhibition of cellular processes

Mechanism of action is to probablyMechanism of action is to probablyinteract with membrane phospholipidsinteract with membrane phospholipids

Have hydrophilic andHave hydrophilic and lipophiliclipophilic

moieties, so can accumulate in cell membranemoieties, so can accumulate in cell membrane


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PeptolidesPeptolides

CyclicCyclic lipopeptidelipopeptide

for IV use infor IV use in

patients with serious grampatients with serious gram--positivepositiveinfectionsinfections

Disrupts cell wall in differentDisrupts cell wall in differentmanner than betamanner than beta--lactamslactams

Low toxicity, muscle achingLow toxicity, muscle aching

Has potential forHas potential for vancomycinvancomycin--

sensitive patients and againstsensitive patients and againstresistant pathogensresistant pathogens


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Metronidazole

Synthetic nitroimidazole antibiotic derived from

azomycin. First found to be active againstprotozoa, and then against anaerobes where it is

still extremely useful.

M t id l


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Metronidazole

Mechanism of Action

Ultimately inhibits DNA synthesis Prodrug which is activated by a reductive process

Selective toxicity against anaerobic and microaerophilic

bacteria due to the presence of ferredoxins which metabolizemetronidazole

Ferredoxins donate electrons to form highly reactive nitro

anion on metronidazole forming cytotoxic products that

interfere with nucleic acid synthesis

Metronidazole displays concentration-dependent

bactericidal activity

M t id l


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Metronidazole

Mechanisms of Resistance well

documented but relatively uncommon

Impaired oxygen scavenging ability

higher local oxygen concentrations whichdecreases activation of metronidazole

Altered ferredoxin levels reducedtranscription of the ferredoxin gene; less

activation of metronidazole

AntiAnti--MycobacterialMycobacterial DrugsDrugs


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MycobacteriaMycobacteria Cause leprosy, tuberculosis, andCause leprosy, tuberculosis, andatypicalatypical mycobacterialmycobacterial

infectionsinfections

MycobacteriaMycobacteria

among the most difficult to cure:among the most difficult to cure:

1) Very slow growing and resistant to antibiotics1) Very slow growing and resistant to antibiotics

2)2) MycobacterialMycobacterial

cells may be dormantcells may be dormant

3) Very lipid3) Very lipid--rich, impermeable cell wallrich, impermeable cell wall

4) Many are intracellular, within macrophages4) Many are intracellular, within macrophages

5) Notorious for ability to develop resistance to any single5) Notorious for ability to develop resistance to any single drugdrug

Remember activity of antibiotics may be dependent on how rapidlyRemember activity of antibiotics may be dependent on how rapidly

the cells are dividing.the cells are dividing.

And thus resistant to many drugs, or killed only very slowly byAnd thus resistant to many drugs, or killed only very slowly by the few active drugs.the few active drugs.

And inaccessible to drugs that penetrate poorly.And inaccessible to drugs that penetrate poorly.

Combinations of drugs required to overcome these obstacles and tCombinations of drugs required to overcome these obstacles and tooprevent emergence of resistant strains.prevent emergence of resistant strains.

IsoniazidIsoniazid probably inhibitsprobably inhibits mycolicmycolicacid synthesisacid synthesis


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acid synthesisacid synthesis

EthambutolEthambutol

Inhibits an enzymeInhibits an enzymeneeded for polymerizationneeded for polymerization

of essential component ofof essential component ofmycobacterialmycobacterial cell wallcell wall

P ra inamidePyrazinamide taken p b macrophages so acti etaken up by macrophages so active


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RifampinRifampin

forms stable complexforms stable complex

with RNA polymerase.with RNA polymerase.

PyrazinamidePyrazinamide

taken up by macrophages, so activetaken up by macrophages, so active

against intracellular organisms residing there.against intracellular organisms residing there.

Unknown mechanism of action.Unknown mechanism of action.

Streptomycin disrupts bacterialStreptomycin disrupts bacterialmembrane and disrupts initiationmembrane and disrupts initiation

of protein synthesis.of protein synthesis.

Leprosy DrugsLeprosy Drugs

i hibi f l h i


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DapsoneDapsone

inhibitsinhibits folatefolate

synthesissynthesis

RifampinRifampin

is also used, usually in combination with another drugis also used, usually in combination with another drug

ClofazimineClofazimine

is a dye with unknown mechanismis a dye with unknown mechanism

Used mainly forUsed mainly for sulfonesulfone--resistant leprosy and also multidrugresistant leprosy and also multidrug--resistant TBresistant TB

Tends to accumulate in skin, so good for leprosyTends to accumulate in skin, so good for leprosy

AA sulfonesulfone

structural analog of Pstructural analog of P--aminobenzoicaminobenzoic

acidacid

Sites of Action of Antibiotics (except

mycobacterials)


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mycobacterials)

peptolidespeptolides

metronidazolemetronidazoleDNA synthesisDNA synthesis

ProteinProtein synthsynth

otherotherQuinupristinQuinupristinDalfopristinDalfopristinLinezolidLinezolidstreptograminsstreptogramins

BacteriostaticBacteriostatic agents minimum inhibitory concentrations generally loweragents minimum inhibitory concentrations generally lowerh b i id l d ith b t i id l d t ti


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than bactericidal drug concentrations.than bactericidal drug concentrations.In general cell wallIn general cell wall--active agents bactericidal and those that inhibit proteinactive agents bactericidal and those that inhibit proteinsynthesissynthesis bacteriostaticbacteriostatic..

BACTERICIDALBACTERICIDAL

AMINOGLYCOSIDESAMINOGLYCOSIDESBACITRACINBACITRACINBETABETA--LACTAMSLACTAMSISONIAZIDISONIAZIDMETRONIDAZOLEMETRONIDAZOLEPOLYMYXINSPOLYMYXINSPYRAZINAMIDEPYRAZINAMIDE

QUINOLONESQUINOLONESRIFAMPINRIFAMPINVANCOMYCINVANCOMYCIN

BACTERIOSTATICBACTERIOSTATIC

CHLORAMPHENICOLCHLORAMPHENICOLETHAMBUTOLETHAMBUTOLOXAZOLIDINONESOXAZOLIDINONESSULFONAMIDESSULFONAMIDESTETRACYCLINESTETRACYCLINESTRIMETHOPRIMTRIMETHOPRIM

MOSTLYMOSTLY

BACTERIOSTATICBACTERIOSTATIC

CLINDAMYCINCLINDAMYCINMACROLIDESMACROLIDESLINEZOLIDLINEZOLIDNITROFURANTOINNITROFURANTOIN

QUINUPRISTINQUINUPRISTIN--DALFOPRISTINDALFOPRISTIN

These are bactericidalThese are bactericidalat high concentrationsat high concentrationsto susceptible organismsto susceptible organisms

protein synth in hib ge recke 2408

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