Antimicrobial drugs

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

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

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

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

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

Inhibitors of Cell Wall Synthesis

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

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.

MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS

The weakness in the cell wall causes the cell to lyze.

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.

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

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

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

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

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

MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGSExamples of aminoglycosides includeGentamicin, streptomycin and tobramycin

Side effects with extended use includeOtotoxicityNephrotoxicity

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

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

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

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

MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGSInhibition of nucleic acid synthesis:

These includeFluoroquinolonesRifamycins

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

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

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

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

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

MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS

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

Antifungal drugs

ClassificationFungal infections traditionally have been

divided into two distinct classes

The major antifungal agents are under

two major headings superficial systemicsystemictopical

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

Systemic antifungal agentsAmphotericin BFlucytosineKetoconazoleMiconazole and Clotrimazole

Antifungal Drugs: OutlinePolyenes (amphotericin B, nystatin)FlucytosineAzoles (imidazoles and triazoles)AllylaminesEchinocandinsGriseofulvinOther drugs

Drug targets

Polyenes:Amphotericin B Chemical properties - amphoteric aqueous insolubility at neutral pH

Antifungal Drugs

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.

Amphotericin B. Fungal resistance Mutants selected in vitro for amphotericin B reisistance replace ergosterol with certain precursor sterols.

Nystatin similar to amphotericin B

used topically and for GI use

used against candida and dermatophytes (Epidermophyton, Trichophyton, Microsporum).

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.

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.

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.

UsesSystemic fungi, mainly candida, and cryptococcus.

Fungistatic.

Used with amphotericin B (cryptococcal meningitis) and with itraconazole (chromoblastomyosis).

AzolesImidazolesTriazoles

Mechanism of action:

Ketoconazole Blastomycosis, coccidioidomycosis, ringworm, candidiasis; given orally.

Acid environment is needed to dissolve drug, does not enter the CNS well.

Mechanism of Action Inhibit the synthesis of ergosterol by blocking demethylation (14-demethylase) of lanosterol - also inhibit cytochrome activity.

Acetyl CoASqualeneLanosterol(ergosterol)AllylaminedrugsSqualene-2,3 oxideSqualene monooxygenase14-a-demethylase

Spectrum of imidazoles Systemic fungi, dermatophytes -fungistatic

Itraconazole: usesHistoplasmosisSporotrichosisAspergillosisBlastomycosisTriazoles (a type of azole)

Topical AzolesClotrimazoleMiconazoleEconazoleOxiconazoleSertaconazole

TerconazoleSulconazoleTioconazoleButoconazole

Allylamines (fungicidal)

Inhibit squalene-2,3-epoxidase

Used to treat dermatophyte infections

Acetyl CoASqualeneLanosterol(ergosterol)AllylaminedrugsSqualene-2,3 oxideSqualene monooxygenase14-a-demethylase

TerbinafineInhibits squalene 2, 3- epoxidase. Squalene is cidal to sensitive organisms.

Used orally for dermatophytes

Adverse effects include hepatitis and rashes. Both are rare.

Naftifine, Amorolfine, and ButenafineOther allylaminesFor topical use

SORDARINS, AZASORDARINSEF3: A target in protein synthesis machinery unique to FUNGI

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.

Mechanism of action binds to microtubules comprising the spindles and inhibits mitosis.

incorporates into keratin and protects newly formed skin.

fungistatic GriseofulvinSpectrum

dermatophytes only

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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