Antimicrobial Drugs
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Transcript of Antimicrobial Drugs
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Antimicrobial drugs
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What are Antibiotics? Where do they come from?Antibiotics are molecules (low molecular weight metabolites) produced by microorganisms that kill other microorganisms or inhibit their growth.Streptomyces, Bacillus, Penicillium, CephalosporiumMany are now semi-synthetic or syntheticAntimicrobial agent, Chemotherapeutic agent
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Ehrlich1ST to use the term chemotherapyCompound 606- arsenic to treat syphilis
DomagkProntosil rubrum SulphanilamideIsoniazid
Fleming, PenicillinFlorey and Chain (penicillin notatum)
Waksman (Schatz) Isolated Streptomyces griseus Streptomycin Coined the term antibiotic 1ST randomized control trial
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SELECTIVE TOXICITYThe Central Concept of antimicrobial action.The growth of the infecting organism is selectively inhibited or the organism is killed without damage to the cells of the host
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Antibiotic ClassificationBactericidal vs. Bacteriostatic-cidal = kills, important for serious infection or when natural ability impaired (diabetes, immune disorders)Beta-lactams, vancomycinAminoglycosides,Rif, Quinolones,Anti-TB drugsAnti-folates (2 used)Tetracyclines, Macrolides,Anti-folates (1 used)-static = inhibits bacterial growth, allowing host defenses to catch up
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MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGSMechanism of action include:Inhibition of cell wall synthesisInhibition of protein synthesisInhibition of nucleic acid synthesisInhibition of metabolic pathwaysInterference with cell membrane integrity
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Inhibitors of Cell Wall Synthesis
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MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGSInhibition of Cell wall synthesis:
Bacteria cell wall unique in constructionContains peptidoglycan
Antimicrobials that interfere with the synthesis of cell wall do not interfere with eukaryotic cellDue to the lack of cell wall in animal cells and differences in cell wall in plant cell
Antimicrobials of this class include lactam drugsVancomycin Bacitracin
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MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGSPenicillins and cephalosporins
Part of group of drugs called lactamsHave shared chemical structure called -lactam ring
Competitively inhibits function of penicillin-binding proteinsInhibits peptide bridge formation between glycan moleculesThis causes the cell wall to develop weak points at the growth sites and become fragile.
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MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS
The weakness in the cell wall causes the cell to lyze.
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MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS
The weakness in the cell wall causes the cell to lyze.
Penicillins and cephalosporins are considered bactericidal. Penicillins are more effective against Gram+ bacteria. This is because Gram + bacteria have penicillin binding proteins on their walls.
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MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGSThe cephalosporinsChemical structures make them resistant to inactivation by certain -lactamases
Tend to have low affinity to penicillin-binding proteins of Gram + bacteria, therefore, are most effective against Gram bacteria.
Chemically modified to produce family of related compoundsFirst, second, third and fourth generation cephalosporins
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MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGSVancomycin
Inhibits formation of glycan chainsInhibits formation of peptidoglycans and cell wall constructionDoes not cross lipid membrane of Gram organisms.
Important in treating infections caused by penicillin resistant Gram + organisms
Acquired resistance most often due to alterations in side chain of NAM moleculePrevents binding of vancomycin to NAM component of glycan
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MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGSBacitracinInterferes with transport of peptidoglycan precursors across cytoplasmic membrane
Toxicity limits use to topical applications
Common ingredient in non-prescription first-aid ointments
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MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGSInhibition of protein synthesis:
Structure of prokaryotic ribosome acts as target for many antimicrobials of this classDifferences in prokaryotic and eukaryotic ribosomes is responsible for selective toxicity
Drugs of this class includeAminoglycosidesTetracyclinsMacrolidsChloramphenicol
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MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGSAminoglycosides
Irreversibly binds to 30S ribosomal subunitCauses distortion and malfunction of ribosomeBlocks initiation translationCauses misreading of mRNA
Not effective against anaerobes, enterococci and streptococci
Often used in synergistic combination with -lactam drugs
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MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGSExamples of aminoglycosides includeGentamicin, streptomycin and tobramycin
Side effects with extended use includeOtotoxicityNephrotoxicity
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MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGSTetracyclinsReversibly bind 30S ribosomal subunitBlocks attachment of tRNA to ribosomePrevents continuation of protein synthesis
Effective against certain Gram + and Gram
Resistance due to decreased accumulation by bacterial cells
Can cause discoloration of teeth if taken by young child
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MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGSMacrolids
Reversibly binds to 50S ribosomePrevents continuation of protein synthesis
Effective against variety of Gram + organisms and those responsible for atypical pneumonia
Often drug of choice for patients allergic to penicillin
Macrolids includeErythromycin, clarithromycin and azithromycin
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MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGSResistance can occur via modification of RNA targetOther mechanisms of resistance include production of enzyme that chemically modifies drug as well as alterations that result in decreased uptake of drug
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MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGSChloramphenicol
Binds to 50S ribosomal subunitPrevents peptide bonds from forming and blocking proteins synthesis
Effective against a wide variety of organisms
Generally used as drug of last resort for life-threatening infections
Rare but lethal side effect is aplastic anemia
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MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGSInhibition of nucleic acid synthesis:
These includeFluoroquinolonesRifamycins
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MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGSFluoroquinolonesInhibit action of topoisomerase DNA gyraseTopoisomerase maintains supercoiling of DNA
Effective against Gram + and Gram
Examples includeCiprofloxacin and ofloxacin
Resistance due to alteration of DNA gyrase
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MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGSRifamycinsBlock prokaryotic RNA polymeraseBlock initiation of transcription
Rifampin most widely used rifamycins
Effective against many Gram + and some Gram - as well as members of genus Mycobacterium
Primarily used to treat tuberculosis and Hansens disease as well as preventing meningitis after exposure to N. meningitidis
Resistance due to mutation coding RNA polymeraseResistance develops rapidly
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MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGSInhibition of metabolic pathways:
Most useful are folate inhibitorsMode of actions to inhibit the production of folic acid
Antimicrobials in this class includeSulfonamidesTrimethoprim
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MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGSSulfonamidesGroup of related compoundsCollectively called sulfa drugs
Inhibit growth of Gram + and Gram - organismsThrough competitive inhibition of enzyme that aids in production of folic acid
Structurally similar to para-aminobenzoic acidSubstrate in folic acid pathway
Human cells lack specific enzyme in folic acid pathwayBasis for selective toxicity
Resistance due to plasmidPlasmid codes for enzyme that has lower affinity to drug
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MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGSTrimethoprim
Inhibits folic acid productionInterferes with activity of enzyme following enzyme inhibited by sulfonamides
Often used synergistically with sulfonamide
Most common mechanism of resistance is plasmid encoded alternative enzymeGenes encoding resistant to sulfonamide and trimethoprim are often carried on same plasmid
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MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS
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MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGSInterference with cell membrane integrity:
Few damage cell membranePolymixn B most commonCommon ingredient in first-aid skin ointments
Binds membrane of Gram - cellsAlters permeabilityLeads to leakage of cell and cell deathAlso bind eukaryotic cells but to lesser extentLimits use to topical application
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Antifungal drugs
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ClassificationFungal infections traditionally have been
divided into two distinct classes
The major antifungal agents are under
two major headings superficial systemicsystemictopical
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ANTIFUNGAL DRUGS--by mode of action
Membrane disrupting agents Amphotericin B, nystatinErgosterol synthesis inhibitorsAzoles, allylamines, morpholineNucleic acid inhibitorFlucytosineAnti-mitotic (spindle disruption)Griseofulvin
Glucan synthesis inhibitorsEchinocandins
Chitin synthesis inhibitorNikkomycin
Protein synthesis inhibitorsSordarins, azasordarins
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Systemic antifungal agentsAmphotericin BFlucytosineKetoconazoleMiconazole and Clotrimazole
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Antifungal Drugs: OutlinePolyenes (amphotericin B, nystatin)FlucytosineAzoles (imidazoles and triazoles)AllylaminesEchinocandinsGriseofulvinOther drugs
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Drug targets
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Polyenes:Amphotericin B Chemical properties - amphoteric aqueous insolubility at neutral pH
Antifungal Drugs
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It binds to a sterol moiety, primarily ergosterol. That is present in the membrane of sensitibe fungi. By virtue of their interaction with the sterols of cell membranes, polyenes appear to form pores or channels. The result is an increase in the permeability of the membrane, allowing leakage of a variety of small molecules, such as Na+. K+. H+ Mechanism of Action Amphotericin B.
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Amphotericin B. Fungal resistance Mutants selected in vitro for amphotericin B reisistance replace ergosterol with certain precursor sterols.
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Nystatin similar to amphotericin B
used topically and for GI use
used against candida and dermatophytes (Epidermophyton, Trichophyton, Microsporum).
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Nystatin Mechanism of action A. Fungistatic and fungicidal B. It binds to sterols, especially ergosterol, which is enriched in the membrane of fungi and yeasts. As a result of this binding, the drug appears to form channels in the membrane that allow small molecules to leak out of the cell.
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Flucytosine Mechanism of actionIt is converted within fungal cells, but not in the hosts cell, to fluorouracil, a metabolic antagonist that ultimately leads to inhibition of thymidylate synthetase.
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Mechanism of action taken up into the fungal cell by means of permease
converted to 5-fluorouracil (5-FU) by cytosine deaminase
5-FU eventually inhibits thymidylate synthetase
synthesized to 5-FUTP
incorporated into RNA.
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UsesSystemic fungi, mainly candida, and cryptococcus.
Fungistatic.
Used with amphotericin B (cryptococcal meningitis) and with itraconazole (chromoblastomyosis).
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AzolesImidazolesTriazoles
Mechanism of action:
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Ketoconazole Blastomycosis, coccidioidomycosis, ringworm, candidiasis; given orally.
Acid environment is needed to dissolve drug, does not enter the CNS well.
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Mechanism of Action Inhibit the synthesis of ergosterol by blocking demethylation (14-demethylase) of lanosterol - also inhibit cytochrome activity.
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Acetyl CoASqualeneLanosterol(ergosterol)AllylaminedrugsSqualene-2,3 oxideSqualene monooxygenase14-a-demethylase
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Spectrum of imidazoles Systemic fungi, dermatophytes -fungistatic
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Itraconazole: usesHistoplasmosisSporotrichosisAspergillosisBlastomycosisTriazoles (a type of azole)
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Topical AzolesClotrimazoleMiconazoleEconazoleOxiconazoleSertaconazole
TerconazoleSulconazoleTioconazoleButoconazole
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Allylamines (fungicidal)
Inhibit squalene-2,3-epoxidase
Used to treat dermatophyte infections
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Acetyl CoASqualeneLanosterol(ergosterol)AllylaminedrugsSqualene-2,3 oxideSqualene monooxygenase14-a-demethylase
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TerbinafineInhibits squalene 2, 3- epoxidase. Squalene is cidal to sensitive organisms.
Used orally for dermatophytes
Adverse effects include hepatitis and rashes. Both are rare.
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Naftifine, Amorolfine, and ButenafineOther allylaminesFor topical use
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SORDARINS, AZASORDARINSEF3: A target in protein synthesis machinery unique to FUNGI
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CaspofunginA large cyclic compound an echinocandin
Inhibits 1,3-b-D-glucan synthase, which is required for glucan polymerization in the wall of certain fungi
Used for aspergillosis and candidiasis
Adverse effects: fever, histamine release, hypokalemiaThis drug that may be synergistic with amphotericin B and the azoles. It has activity against Candida species and Aspergillus species.
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Mechanism of action binds to microtubules comprising the spindles and inhibits mitosis.
incorporates into keratin and protects newly formed skin.
fungistatic GriseofulvinSpectrum
dermatophytes only
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Other Drugs
Ciclopirox olamine - may block amino acid transport - penetrates well - useful for candida and dermatophytes
Haloprogin - useful for dermatophytes and candida, may cause burning
Tolnaftate - useful for dermatophytes - inhibits synthesis of macromolecules
Undecylenic acid - dermatophytes
KI - taken orally for cutaneous sporotrichosis - may cause a rash and irritation of salivary and lacrimal glands
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