MICROLEC: LEC

WEEK 2 :ANTIMICROBIAL DRUGS

Objectives:

1. To discuss the history of antimicrobial agents.

2. To explain the mechanisms of action of antimicrobial drugs.
3. To enumerate and explain clinical considerations in the use of antimicrobial drugs.
4. To discuss the concept of resistance.

Definition of Terms

 DRUGS – chemicals that affect physiology in any manner (caffeine, alcohol, tobacco)
 Chemotherapeutic Agents – drugs that act against diseases
 Antimicrobial Agents – drugs for treating infections

History of Antimicrobial Drugs

 Ehrlich – proposed the term chemotherapy

 Fleming (1929) – coined the term antibiotics – antimicrobial agents that are produced
naturally by an organism
 Gerhard Domagk (1932) – discovered sulfanilamide
 Penicillin (1940s)- became available in large quantities
 Semi synthetics – chemically modified antibiotics
 Synthetics – antimicrobials that are completely synthesized in a laboratory.

*** More than half of all antibiotics and semi synthetics are derived from species of
Streptomyces

Mechanisms of Action of Antimicrobial Drugs

1. Inhibition of Cell Wall Synthesis

 Cell Wall – Peptidoglycan: N-acetylglucosamine (NAG) and N-acetylmuramic acid
(NAM)
 Beta-lactams - inhibit peptidoglycan formation by irreversibly binding to the
enzymes that crosslink NAM sub-unit.
 Vancomycin and Cycloserine – disrupted cell wall formation by interfering with
alanine-alanine bridges that link NAM sub-units in many Gram (+) bacteria.
 Bacitracin –disrupts cell wall formation by blocking the secretion of NAG and
NAM from the cytoplasm.
 Isoniazid and Ethambutol – block mycolic acid synthesis in the walls of
Mycobacteria.

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2. Inhibition of CHON Synthesis

 Prokaryotic Ribosomes 70s (30s & 50s subunits)
 Eukaryotic Ribosomes 80s (40s & 60s)
 Aminoglycosides/Tetracyclines – target the 30s ribosomal subunit
3. Disruption of Cytoplasmic Membranes
 By becoming incorporated into the membrane & damaging its integrity
 Polyenes (e.g. Amphotericin B) – fungicidal because it attaches to ergosterol, a
lipid constituent of fungal membranes
 Polymyxin – effective against Gram (-) bacteria, but is toxic to human kidneys
4. Inhibition of Metabolic Pathways
 Antimetabolic agents target differences between metabolic processes of a pathogen
and its host
 Sulfonamides – are natural analogs of para-amino-benzoic acid (PABA), a
compound that is crucial in DNA and RNA synthesis in some microorganism, but
not in humans.
 Trimethoprim/Amantadine/Rimantadine/Weak Organic Bases – are used an
antiviral drugs because they can neutralize acidic environment of phagolysosomes
and thus prevent viral uncoating.
5. Inhibition of Nucleic Acid Synthesis
 Nucleotide Analogs – are incorporated into the DNA and RNA of pathogens, where
they distort the shapes of nucleic acid molecules
 Quinolones/Fluoroquinolones – they inhibit DNA gyrase, an enzymes important
for correct coiling of replicating bacterial DNA.
6. Prevention of Virus attachment
 Attachment Antagonists (Arildone) – block attachment molecule on host cell
pathogen

Clinical Considerations Prescribing Antimicrobial Drugs

 Ideal antimicrobial agent:

o Readily available
o Inexpensive
o Chemically stable
o Easily administered
o Non-toxic and Non-allergic
o Selectively toxic against wide range of pathogens
 Spectrum of Action
 Efficacy
 Routes of Administration
 Safety & Side Effects

Resistance

 Microorganisms may resist a drug by any 1 of 5 mechanisms by:

1. Producing enzymes

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2. Inducing changes in the cell membrane that prevent entry drug

3. Alternating the drug’s receptor to prevent its binding
4. Alternating the cell’s metabolic pathways
5. Pumping the drug out of the cell

Retarding Resistance

 Resistance can be retarded in 1 or more of 4 ways by:

1. Using sufficiently high concentrations of a drug for a sufficient time to kill all sensitive
cells and inhibit other long enough for the body’s defenses to destroy them.
2. Using antimicrobials in combinations, promoting SYNERGISM – the interplay between
drugs that result in efficacy that exceeds the efficacy of either drug alone.
3. Limiting the use of antimicrobials to necessary cases, avoiding indiscriminate
prescribing and uncontrolled use.
4. Developing new variations of existing drugs.

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