Antimikroba

Antimikroba

dr. Rohmania Setiarini

Definition

• Chemotherapeutic agents– Drugs that act against diseases

• Antimicrobial agents – Drugs that treat infections• Antibiotics

• Antimicrobial agents produced naturally by organisms

• Semisynthetics– Chemically altered antibiotics that are more effective than

naturally occurring ones• Synthetics

– Antimicrobials that are completely synthesized in a lab

• 1928 – Fleming discovered penicillin, produced by Penicillium.

• 1940 – Howard Florey and Ernst Chain performed first clinical trials of penicillin.

Features of Antimicrobial Drugs• Selective toxicity

– Antibiotics cause greater harm to microorganisms than to human host

– Toxicity of drug is expressed as therapeutic index• Lowest dose toxic to patient divided by dose typically

used for treatment– High therapeutic index = less toxic to patient– Narrow therapeutic index = more toxic, monitor closely

Features of Antimicrobial Drugs

• Antimicrobial action– Bacteriostatic drugs

• Inhibit bacterial growth• rely on host immunity

– Bacteriocidal drugs • Kill bacteria• Most useful in situations when host defenses cannot

control pathogen

Classification of antibacterial agents:

bactericidalβ-lactam agents Aminoglycosides Co-trimoxazoleVancomycin

bacteriostatic• Erythromycin• Tetracycline• Chloramphenicol• Sulfonamide• Trimethroprim


• Spectrum of activity– Antimicrobials vary with respect to range of

organisms controlled• Narrow spectrum

– Work on narrow range of organisms» Gram-positive only OR Gram-negative only

– Advantage: effects pathogen only– Disadvantage: requires identification of pathogen

• Broad spectrum– Advantage: Work on broad range of organisms– Disadvantage : disruption of normal flora


• Effects of combinations of antimicrobial drugs– Combination sometimes used to treat infections

• Synergistic: whole is > sum• Antagonistic: whole is < sum

Effects of Combinations of Drugs


• Tissue distribution, metabolism and excretion– Drugs differ in how they are distributed,

metabolized and excreted– Half-life: Rate of elimination of drug from body

• Time it takes for the body to eliminate one half the original dose in serum

• Half-life dictates frequency of dosage– Patients with liver or kidney damage tend to

excrete drugs more slowly


• Adverse effects– Allergic reactions– Toxic effects– Suppression of normal flora– Antimicrobial resistance

Figure 10.2 Mechanisms of action of microbial drugs

Humancell membrane

Inhibition of pathogen’sattachment to, orrecognition of, hostArildonePleconaril

Inhibition of cellwall synthesisPenicillinsCephalosporinsVancomycinBacitracinIsoniazidEthambutolEchinocandins(antifungal)

Inhibition of DNAor RNA synthesisActinomycinNucleotide analogsQuinolonesRifampin

Inhibition of generalmetabolic pathwaySulfonamidesTrimethoprimDapsone

Disruption ofcytoplasmic membranePolymyxinsPolyenes (antifungal)

Inhibition ofprotein synthesisAminoglycosidesTetracyclinesChloramphenicolMacrolides

Mechanisms of Antimicrobial Action

• Inhibition of Cell Wall Synthesis– Inhibition of bacterial wall synthesis

• Most common agents prevent cross-linkage of NAM subunits

• Beta-lactams are most prominent in this group– Functional groups are beta-lactam rings– Beta-lactams bind to enzymes that cross-link NAM

subunits• Bacteria have weakened cell walls and eventually lyse

© 2012 Pearson Education Inc.

Structural formulas of some beta-lactam drugs

Penicillin G (natural)

Methicillin (semisynthetic)

Penicillins Cephalosporin Monobactam

-lactam ring

Cephalothin (semisynthetic) Aztreonam (semisynthetic)

The effect of penicillin on peptidoglycan in preventing NAM-NAM cross-links

Penicillin interferes with the linking enzymes,and NAM subunits remain unattached to theirneighbors. However, the cell continues togrow as it adds more NAG and NAM subunits.

Growth

The cell bursts from osmoticpressure because the integrity ofpeptidoglycan is not maintained.

New NAM-NAMcross-linksinhibited bypenicillin

Previously formedcross-links remainunchanged


• Inhibition of Cell Wall Synthesis– Inhibition of synthesis of bacterial walls

• Semisynthetic derivatives of beta-lactams – More stable in acidic environments– More readily absorbed– Less susceptible to deactivation– More active against more types of bacteria

• Simplest beta-lactams – effective only against aerobic Gram-negatives



• Vancomycin and cycloserine – Interfere with bridges that link NAM subunits in many

Gram-positives• Bacitracin

– Blocks secretion of NAG and NAM from cytoplasm• Isoniazid and ethambutol

– Disrupt mycolic acid formation in mycobacterial species



• Prevent bacteria from increasing amount of peptidoglycan

• Have no effect on existing peptidoglycan layer• Effective only for growing cells

Protein Synthesis Inhibitors


• Disruption of Cytoplasmic Membranes– Some drugs form channel through cytoplasmic

membrane and damage its integrity– Amphotericin B attaches to ergosterol in fungal

membranes

Figure 10.5 Disruption of the cytoplasmic membrane by amphotericin B-overview


• Disruption of Cytoplasmic Membranes– Azoles and allylamines inhibit ergosterol synthesis– Polymyxin disrupts cytoplasmic membranes of

Gram-negatives• Toxic to human kidneys

– Some parasitic drugs act against cytoplasmic membranes


• Inhibition of Metabolic Pathways– Antimetabolic agents can be effective when

metabolic processes of pathogen and host differ– Quinolones interfere with the metabolism of

malaria parasites– Agents that disrupt tubulin polymerization and

glucose uptake by many protozoa and parasitic worms

– Drugs block activation of viruses– Metabolic antagonists

Figure 10.6 Antimetabolic action of sulfonamides-overview


• Inhibition of Nucleic Acid Synthesis– Quinolones and fluoroquinolones

• Act against prokaryotic DNA gyrase– Inhibitors of RNA polymerase during

transcription– Reverse transcriptase inhibitors

• Act against an enzyme HIV uses in its replication cycle• Do not harm people because humans lack reverse

transcriptase

Spectrum of action for selected antimicrobial agents

• Ideal Antimicrobial Agent– Readily available– Inexpensive– Chemically stable– Easily administered– Nontoxic and nonallergenic– Selectively toxic against wide range of pathogens

Antimikroba

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