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 gerecke@eohsi.rutgers.edugerecke@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
70S initiation complex70S 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
30S initiation complex30S initiation complex
70S initiation complex70S 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
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
transferasetransferase
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
transferasetransferase
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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AminoglycosidesAminoglycosides
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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AminoglycosidesAminoglycosides
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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Inhibitors of Protein SynthesisInhibitors of Protein Synthesis
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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Inhibitors of Protein SynthesisInhibitors of Protein Synthesis
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
transferasetransferase
((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
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