Antimicrobial Agents: Mechanisms, History, and Resistance 20

The History of Antimicrobial Agents CH 20

Early Discoveries and Key Figures

The development of antimicrobial agents revolutionized the treatment of infectious diseases. The following are key milestones and contributors in the history of antimicrobial therapy:

• Paul Ehrlich: Developed the concept of the "Magic Bullet"—a compound that selectively targets pathogens without harming the host. He discovered Salvarsan, effective against Trypanosomes and Treponemes.

• 1928: Alexander Fleming: Discovered penicillin, the first antibiotic derived from a mold (Penicillium).

• 1940: Howard Florey and Ernst Chain: Performed the first clinical trials of penicillin, demonstrating its effectiveness.

• Sulfanilamide: The first antimicrobial agent used to treat a wide array of infections.

Antibiotics are antimicrobial agents produced naturally by organisms, while antimicrobial drugs include both natural and synthetic chemicals.

Mechanisms of Selective Toxicity

Key Principles

Selective toxicity is the ability of a drug to target microbial cells without harming host cells. This principle underlies the effectiveness of antimicrobial agents.

• Selective Toxicity: Drugs exploit differences between microbial and host cells.

• Fewer drugs are available for treating eukaryotic infections due to similarities with human cells.

• Antiviral drugs are limited, with most targeting HIV.

Inhibition of Cell Wall Synthesis

Beta-Lactam Antibiotics

Many antibiotics inhibit cell wall synthesis, a process unique to bacteria, making it an excellent target for selective toxicity.

• Beta-lactams (e.g., penicillins, cephalosporins): Prevent cross-linkage of NAM subunits in peptidoglycan, weakening the cell wall.

• Beta-lactam rings are essential for activity; functional groups vary among beta-lactam drugs.

• Some bacteria produce beta-lactamases that inactivate these drugs.

• Other drugs: Vancomycin (binds D-Ala-D-Ala), Bacitracin (blocks transport of peptidoglycan precursors).

Example: Penicillin is effective against Gram-positive bacteria due to their thick peptidoglycan layer.

Inhibition of Protein Synthesis

Targeting Bacterial Ribosomes

Antibiotics can selectively inhibit bacterial protein synthesis by targeting the 70S ribosome, which differs from the 80S ribosome in eukaryotes.

• Aminoglycosides (e.g., streptomycin): Bind 30S subunit, causing misreading of mRNA.

• Tetracyclines: Block tRNA attachment to the ribosome.

• Macrolides (e.g., erythromycin): Bind 50S subunit, inhibiting translocation.

• Chloramphenicol: Inhibits peptide bond formation.

• Oxazolidinones: Prevent formation of the initiation complex.

Example: Mitochondria in eukaryotic cells contain 70S ribosomes, so some antibiotics can have side effects on human cells.

Disruption of Cytoplasmic Membranes

Membrane-Targeting Drugs

Some antibiotics disrupt the integrity of microbial membranes, leading to cell death.

• Polymyxins: Disrupt cytoplasmic membranes of Gram-negative bacteria.

• Can be toxic to human kidneys due to lack of selectivity.

Inhibition of Metabolic Pathways

Antimetabolites

These drugs interfere with microbial metabolism by mimicking or blocking key enzymes.

• Trimethoprim: Inhibits dihydrofolate reductase, blocking folic acid synthesis.

• Sulfonamides: Block folic acid synthesis at an earlier step.

• Humans obtain folic acid from diet, so these drugs are selectively toxic to bacteria.

Inhibition of Nucleic Acid Synthesis

Targeting DNA and RNA Synthesis

Some drugs inhibit the synthesis of nucleic acids, affecting DNA replication or transcription.

• Quinolones and fluoroquinolones: Inhibit prokaryotic DNA gyrase.

• Rifampin: Inhibits RNA polymerase, used in tuberculosis treatment.

Antiviral Drugs: Enzyme Inhibitors

Targeting Viral Enzymes

Antiviral drugs often inhibit enzymes unique to viruses.

• Protease inhibitors: Block viral protease enzymes (e.g., HIV treatment).

• Integrase inhibitors: Prevent integration of viral DNA into host genome.

• Reverse transcriptase inhibitors: Block reverse transcription in retroviruses.

Inhibition of Nucleic Acid Synthesis (Antiviral)

Nucleoside Analogs

These drugs mimic nucleotides, interfering with viral replication.

• Cause premature chain termination or faulty replication.

• Some are used against rapidly dividing cancer cells.

Prevention of Virus Attachment

Entry Inhibitors

Some antiviral drugs block viral entry into host cells by interfering with attachment or fusion.

• Peptide and sugar analogs block viral receptors.

• Examples: Amantadine (influenza), Enfuvirtide (HIV), Maraviroc (HIV).

Antifungal Drugs

Selective Toxicity and Mechanisms

Antifungal drugs exploit differences between fungal and human cells, such as ergosterol in fungal membranes.

• Polyenes (e.g., amphotericin B): Bind ergosterol, disrupting membrane integrity.

• Azoles: Inhibit ergosterol synthesis.

• Allylamines: Also inhibit ergosterol synthesis.

The Spectrum of Antimicrobial Activity

Broad vs. Narrow Spectrum

Antimicrobial drugs vary in the range of organisms they affect.

• Broad-spectrum drugs: Effective against a wide variety of microbes.

• Narrow-spectrum drugs: Target specific types of bacteria.

Measuring Antimicrobial Effectiveness

Key Terms and Methods

• MIC (Minimal Inhibitory Concentration): Lowest concentration of a drug that inhibits visible growth of a microorganism.

• MBC (Minimal Bactericidal Concentration): Lowest concentration that kills 99.9% of the bacteria.

• Antibigram: A chart showing the susceptibility of bacteria to various antibiotics.

Antibiotic Resistance

Mechanisms and Causes

Antibiotic resistance arises through genetic mutations and horizontal gene transfer. Resistance genes are often located on plasmids or transposons.

• Misuse of antibiotics selects for resistant strains.

• Common causes: Using outdated/weakened antibiotics, inappropriate prescriptions, not completing prescribed regimens, and using leftover prescriptions.

Effects of Combination of Drugs

Synergism and Antagonism

• Synergism: The effect of two drugs together is greater than the effect of either alone.

• Antagonism: The effect of two drugs together is less than the effect of either alone.