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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 toxicity
Selective
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:
bactericidal

bacteriostatic

-lactam agents
Aminoglycosides
Co-trimoxazole
Vancomycin

Erythromycin
Tetracycline
Chloramphenicol
Sulfonamide
Trimethroprim

Features of Antimicrobial
Drugs
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

Features of Antimicrobial
Drugs
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

Features of Antimicrobial
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

Features of Antimicrobial
Drugs
Adverse effects

Allergic reactions
Toxic effects
Suppression of normal flora
Antimicrobial resistance

Figure 10.2 Mechanisms of action of microbial drugs

Inhibition of cell
wall synthesis
Penicillins
Cephalosporins
Vancomycin
Bacitracin
Isoniazid
Ethambutol
Echinocandins
(antifungal)

Inhibition of pathogens
attachment to, or
recognition of, host
Arildone
Pleconaril

Inhibition of
protein synthesis
Aminoglycosides
Tetracyclines
Chloramphenicol
Macrolides

Human
cell membrane

Inhibition of DNA
or RNA synthesis
Actinomycin
Nucleotide
analogs
Quinolones
Rifampin

Disruption of
cytoplasmic membrane
Polymyxins
Polyenes (antifungal)

Inhibition of general
metabolic pathway
Sulfonamides
Trimethoprim
Dapsone

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 crosslink NAM subunits

Bacteria have weakened cell walls and


eventually lyse

2012 Pearson Education Inc.

Structural formulas of some beta-lactam drugs

-lactam ring
Penicillin G (natural)

Cephalothin (semisynthetic)

Aztreonam (semisynthetic)

Cephalosporin

Monobactam

Methicillin (semisynthetic)

Penicillins

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

Penicillin interferes with the linking enzymes,


and NAM subunits remain unattached to their
neighbors. However, the cell continues to
grow as it adds more NAG and NAM subunits.

The cell bursts from osmotic


pressure because the integrity of
peptidoglycan is not maintained.

Growth

New NAM-NAM
cross-links
inhibited by
penicillin

Previously formed
cross-links remain
unchanged

Mechanisms of Antimicrobial Action


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

Mechanisms of Antimicrobial Action


Inhibition of Cell Wall Synthesis
Inhibition of synthesis of bacterial walls
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

Mechanisms of Antimicrobial Action


Inhibition of Cell Wall
Synthesis
Inhibition of synthesis of bacterial
walls
Prevent bacteria from increasing amount
of peptidoglycan
Have no effect on existing peptidoglycan
layer
Effective only for growing cells

Protein Synthesis Inhibitors

Mechanisms of Antimicrobial Action


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

Mechanisms of Antimicrobial Action


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

Mechanisms of Antimicrobial Action

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

Mechanisms of Antimicrobial Action


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