Chapter 12 Antimicrobial Agent Mechanisms of Action and Resistance - PowerPoint Presentation

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Chapter 12 Antimicrobial Agent Mechanisms of Action and Resistance - PPT Presentation

Copyright 2015 by Saunders an imprint of Elsevier Inc Introduction Antimicrobial agents Chemical compounds to kill or suppress microorganisms Antibiotics Natural semisynthetic or synthetic molecules used to treat or prevent disease ID: 779421

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Chapter 12

Antimicrobial Agent Mechanisms of Action and Resistance

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IntroductionAntimicrobial agentsChemical compounds to kill or suppress microorganismsAntibioticsNatural, semisynthetic, or synthetic molecules used to treat or prevent disease ResistanceIntrinsic resistanceNaturally found in bacteria (chromosomal)Acquired resistanceAcquired from exogenous DNA (plasmid or through conjugation)

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Antibiotic Targets and Mechanism of ActionApproximately 23 unique classes and 18 subclasses of clinically useful antibioticsTwo basic activitiesCell wallInterference or disruption of cell integrity by disrupting cell wall or cell membrane Metabolic functionsInterruption of basic metabolic functions such as protein synthesis, nucleic acid metabolism, and inhibition of essential metabolitesSee Table 12-1

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Antibiotic Targets and Mechanism of Action (Cont.)

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Antibiotic Targets and Mechanism of Action (Cont.)

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Antibiotic Targets and Mechanism of Action (Cont.)

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Inhibition of Bacterial Cell Wall BiosynthesisCell wall protects bacteria.Specific integral enzymes are necessary to build and shape the cell wall.Transpeptidases: cross-link the cell wallThese enzymes are also called penicillin binding proteins (PBPs).Specific to each bacteria, therefore drugs may have difference in binding to each PBP and thus have different levels of effectivenessDrugs are designed to inhibit and inactivate these enzymes.

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Cell Wall Structure

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Inhibition of Bacterial Cell Wall Biosynthesis (Cont.)Peptidoglycan biosynthesis stagesSynthesis of precursors in the cytoplasmTransport of lipid-bound precursors across the cytoplasmic membraneD-cycloserine and bacitracin inhibit steps 1 and 2.Insertion of glycan units into the cell wallTranspeptidation linking and maturation -lactams and glycopeptides inhibit steps 3 and 4.

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Cell Wall Structure (Cont.)

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Inhibition of Bacterial Cell Wall Biosynthesis (Cont.)β-lactam antibioticsNatural and semisyntheticPenicillins, cephalosporins, carbapenems, monobactamsBased on chemical structure, the β-lactam ringBind to and inhibit the transpeptidases (PBPs)

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Inhibition of Bacterial Cell Wall Biosynthesis (Cont.)β-lactams must pass through cell wall porins in gram-negative cells to reach cell PBPs.The binding of the type of β-lactam to specific PBPs influences effectiveness of certain drugs on specific organisms.ExampleMonobactam (aztreonam)Binds primarily to PBP of gram-negative aerobesNo activity against gram-positive because incorrect PBPs

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Examples of β-Lactam Antibiotics

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Examples of β-Lactam Antibiotics (Cont.)

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Chemical Structures of β-Lactam Antibiotics

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Inhibition of Bacterial Cell Wall Biosynthesis (Cont.)Narrow spectrumWork only on gram-positives (cannot penetrate the outer cell membrane)Broad spectrumWork on a broad variety of bacteria (can penetrate the outer membrane)

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Inhibition of Bacterial Cell Wall Biosynthesis (Cont.)GlycopeptidesVancomycinTeicoplaninBlock transpeptidation stepNarrow spectrum antibioticUseful for staphylococci, streptococci, and enterococci

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Inhibition of Folate SynthesisFolinic acid Necessary for the synthesis of bacterial DNAMost make their own; very few can acquire it from the environmentPara-aminobenzoic acid to folinic acidSulfonamidesSulfamethoxazole (SMZ)Competitively inhibits dihydropteroate synthetaseNeed constant levels of drug to inhibit enzyme

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Inhibition of Folate Synthesis (Cont.)Trimethoprim (TMP)Competitively inhibits dihydrofolate reductaseNeeds constant levels of drug to inhibit enzymeUsing these in combination as a synergistic effectSynergyCombined effect is greater than the additive effectEnhanced activity

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Inhibition of Folate Synthesis (Cont.)

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Interference with DNA ReplicationDisruption of DNA synthesisDisruption of replicationNalidixic acid and fluorinated quinolonesTarget type II (DNA gyrase) and IV topoisomerase enzymesUse in treatment of Enterobacteriaceae, pseudomonads, staphylococci, enterococci, neisseria, and streptococci species other than S. pneumoniaeTrap enzymes as stable reaction intermediates inhibiting DNA replication through bacteriostasis

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Interference with DNA TranscriptionRifampinSynthetic derivative of rifamycin BInterferes with production of mRNAThus prevents protein synthesis via blocking RNA polymerase

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Interference with DNA TranslationBind to the 50S or 30S ribosomal subunitCan be reversible or irreversibleAminoglycosidesIrreversibly binds to 30S subunitPrevents docking of aminoacyl-tRNAAlso contributes to misreading the genetic codeSpectinomycinBinds 30S subunit Interferes with the stability of peptidyl tRNA by inhibiting elongation factor

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Interference with DNA Translation (Cont.)Tetracyclines Tetracycline, doxycycline, minocyclineReversible binding to 30S subunitInhibit rotation of bound tRNA into the A siteCauses premature release of peptidesMacrolidesErythromycin, clarithromycin, azithromycinReversibly binds to the 50S subunitPrevent elongation by blocking exit sitePrevent ribosome assemblyInterference and antagonism can occur if used in combination with each other.

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Interference with DNA Translation (Cont.)KetolidesSemisynthetic compoundTelithromycinBinds to the 50S subunitInhibits RNA-dependent protein synthesisEvade macrolide-resistance mechanisms Through improved ribosome binding affinity Evasion of macrolide efflux mechanisms

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Recently Approved Classes of Antibiotics Targeting Protein SynthesisOxazolidinonesLinezolidActivity against gram-positive bacteria by binding 50S subunit and blocking initiation and translocationMRSA, steptococcal pneumonia, M. TuberculosisStreptogramin70:30 mixture of A and B molecules called Dalfopristin-quinupristinDisrupt translation by blocking elongation and binding of aminoacyl-tRNADalfopristin helps quinupristin bind with greater affinity.

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Recently Approved Classes of Antibiotics Targeting Protein Synthesis (Cont.)GlycylcyclineTigecyclineHigher affinity for 30S ribosomal subunit than tetracyclineIncreased effectiveness against tetracycline-resistant organismsWide spectrum of activity against gram-positive, gram-negative, and atypical pathogens

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Mechanisms of Antibiotic ResistanceIntrinsic resistanceNaturally found in bacteria (chromosomal)Acquired resistanceAcquired from exogenous DNA (plasmid, conjugation, transposons, bacteriophage, etc.)

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Origins of Antibiotic ResistanceSome resistance is 2000 years oldCanadian glaciersSome resistance in deep sea areas is 10,000 years oldNear Papua New GuineaEvolution of resistanceMay have occurred as a way to prevent autotoxicity

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Intrinsic Mechanisms of ResistanceMechanisms of resistanceLack of affinity of the drug for the bacterial targetPrevent access of drug to relevant site of actionCell walls, membranes, biofilmsBiofilmsSessile bacterial communities that are irreversibly attached to a solid surface and are embedded in an exopolysaccharide matrix

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Intrinsic Mechanisms of Resistance (Cont.)EffluxIncrease secretion of drugFive major subfamiliesEnzymatic inactivationProduce enzymes that destroy the drugExampleβ-lactamases

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β-Lactamase

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Current β-Lactamase Classification Scheme

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Current β-Lactamase Classification Scheme (Cont.)

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Acquired Mechanisms of ResistanceEfflux pumpsIncrease secretion of drugTarget site modificationUsually occurs by chromosomal mutationMutations that reduce effectiveness of drug to act on its targetProduction of enzymes that alter target Reduce effectiveness of drug to act on its target

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Acquired Mechanisms of Resistance (Cont.)Enzymatic target site alterationEnzymes alter antibiotic targets resulting in reduced affinity and effectivenessAcquisition of new targetsMicroorganisms acquire new cellular targets with reduced affinity to antibiotic.Transfer of mobile genetic elementsTarget site substitutionAcquisition of a new enzyme that is unaffected by drugs or creates a new pathway

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Acquired Mechanisms of Resistance (Cont.)Enzymatic inactivation of antibioticsEnzymes produced by the microorganisms inactivate antibiotics directly.Destroy antibioticModification rendering it ineffectiveAcquisition of new targetsMicroorganisms acquire new cellular targets with reduced affinity to antibiotic.Transfer of mobile genetic elementsTarget site substitutionAcquisition of a new enzyme that is unaffected by drugs or creates a new pathway

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DisseminationLateral gene transfer (LGT)Two processesPhysical movementIncorporation into genomeMechanisms of transferPlasmidsTransformation or conjugationTransposons (Tn)Mobile genetic elementsContain transposase for nonhomologous recombinationInsertion sequencesExample NR1 in Shigella flexneri

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Dissemination (Cont.)Mechanisms of transferIntegronsGenetic elements that capture mobile gene cassettes by site-specific recombinationSite-specific recombinase (IntI)Primary recombination site (attI)Insertion sequencesShort DNA sequences that act as simple transposable elements

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Nanotechnology to Deliver Therapeutic AgentsTechnology potentialNew ways to deliver drugsImprove circulation timeImprove drug localization within the bodyImprove solubility and pharmacokinetic profileDrug delivery mechanismsLiposomesNanotubesNanoshellsCochleates