Chapter 10: Controlling Microbial Growth in the Body

Introduction to Antimicrobial Drugs

Antimicrobial drugs are chemicals used to control the growth of microbes within the body without causing harm to the host. The central principle guiding their use is selective toxicity, which means the drug targets the pathogen while sparing host cells. These drugs are a cornerstone of modern medicine, drastically reducing mortality from infectious diseases.

History and Sources of Antimicrobial Agents

• Salvarsan (arsphenamine) was the first modern chemotherapeutic agent, used to treat syphilis (1910).

• Penicillin, discovered by Alexander Fleming in 1929, was the first true antibiotic and became widely available in the 1940s.

• Sulfanilamide (1932) was the first widely available antimicrobial agent, inhibiting nucleotide synthesis.

• Most antimicrobials are secondary metabolites produced by fungi and bacteria, which naturally compete with other microbes in their environment.

Key Factors for Antimicrobial Action

• Selective toxicity is essential—drugs must kill or inhibit pathogens without damaging the host.

• Antibacterial drugs are the most numerous and diverse, while antifungal, antiprotozoan, antihelminthic, and antiviral drugs are less common due to similarities between eukaryotic pathogens and host cells.

Mechanisms of Antimicrobial Action

Antimicrobial drugs target structures or processes unique to microbes. The main mechanisms include:

• Inhibition of cell wall synthesis

• Inhibition of protein synthesis

• Disruption of cytoplasmic membranes

• Inhibition of metabolic pathways

• Inhibition of nucleic acid synthesis

• Inhibition of pathogen attachment or recognition

Inhibition of Cell Wall Synthesis

Most cell wall inhibitors prevent the cross-linking of N-acetylmuramic acid (NAM) subunits in peptidoglycan, weakening the bacterial cell wall and causing lysis. Beta-lactam antibiotics (e.g., penicillins, cephalosporins) are the most prominent group, binding to enzymes that cross-link NAM subunits.

• These drugs are effective only against growing cells and do not affect existing peptidoglycan layers.

• They do not affect animal or plant cells, which lack peptidoglycan.

• Semisynthetic derivatives are more stable, better absorbed, and have a broader spectrum of activity.

Inhibition of Protein Synthesis

Prokaryotic ribosomes (70S) differ from eukaryotic ribosomes (80S), allowing selective targeting. However, mitochondria in eukaryotes also contain 70S ribosomes, which can lead to side effects.

• Examples include aminoglycosides (e.g., streptomycin), tetracyclines, chloramphenicol, macrolides (e.g., erythromycin), and antisense RNA.

• These drugs interfere with various steps of translation, such as mRNA reading, tRNA docking, peptide bond formation, and ribosome movement.

Disruption of Cytoplasmic Membranes

Certain drugs, such as Amphotericin B, bind to ergosterol in fungal membranes, forming pores and causing cell leakage. Human cells are less affected due to the presence of cholesterol instead of ergosterol, but some toxicity can occur.

Inhibition of Metabolic Pathways

Antimetabolic agents target differences in metabolic enzymes between pathogens and hosts. Examples include:

• Heavy metals that inactivate enzymes

• Drugs that paralyze parasitic worms

• Agents that block viral activation

• Metabolic antagonists (e.g., sulfa drugs, trimethoprim) that inhibit folic acid synthesis, crucial for nucleotide biosynthesis

Inhibition of Nucleic Acid Synthesis

Nucleic acid analogs mimic normal nucleotides but lack essential atoms, causing premature termination of DNA or RNA synthesis. Viral polymerases are especially susceptible due to their error-prone nature.

• Examples: Acyclovir (herpes), Remdesivir (COVID-19), Retrovir (HIV)

Inhibition of Pathogen Attachment

Some drugs prevent viruses from attaching to or releasing from host cells. For example, neuraminidase inhibitors (e.g., Relenza, Tamiflu) block the release of influenza virions, preventing further infection.

Spectrum of Action

Antimicrobial drugs vary in their spectrum of activity. Broad-spectrum drugs target a wide range of organisms but may disrupt normal flora, leading to secondary infections. Narrow-spectrum drugs are more selective.

Efficacy of Antibacterial Agents

Several laboratory tests are used to determine the effectiveness of antibiotics:

• Disk-diffusion (Kirby-Bauer) test: Measures the zone of inhibition around antibiotic disks on an agar plate.

• Minimum inhibitory concentration (MIC) test: Determines the lowest concentration of drug that inhibits visible growth.

• Minimum bactericidal concentration (MBC) test: Determines the lowest concentration that kills the bacterium.

Administration of Antimicrobial Drugs

To be effective, the drug must reach the site of infection at a concentration above the MIC. Routes of administration include:

• Topical (local): Direct application to skin or mucous membranes

• Oral: Convenient but patient compliance may vary

• Intramuscular (IM): Injection into muscle tissue

• Intravenous (IV): Directly into the bloodstream, achieving the highest and fastest drug levels

Safety and Side Effects

Antimicrobial drugs can have adverse effects, including:

• Toxicity: Some drugs are toxic to kidneys, liver, or nerves; tetracyclines can damage teeth and bones; metronidazole can cause darkening of the tongue.

• Allergies: Rare but potentially life-threatening reactions.

• Disruption of normal flora: Can lead to overgrowth of opportunistic pathogens, such as Candida albicans (yeast infections) or Clostridium difficile (pseudomembranous colitis).

Development of Resistant Organisms

Bacteria can acquire resistance through spontaneous mutations or by obtaining resistance genes via transformation, transduction, or conjugation. Resistance spreads when resistant microbes become the majority, often due to incomplete treatment or overuse of antibiotics.

Bacterial Resistance Mechanisms

• Production of enzymes (e.g., beta-lactamase) that inactivate antibiotics

• Prevention of drug entry by altering membrane proteins

• Alteration of drug targets within the cell

• Changes in metabolic pathways

• Efflux pumps that expel drugs from the cell

Methods for Retarding Resistance

• Maintain high drug concentrations for sufficient time to kill all sensitive cells

• Use combinations of drugs (synergism)

• Limit antimicrobial use to necessary cases

• Develop new drugs or modify existing ones (second- and third-generation drugs)

• In extreme cases, use anti-cancer drugs as antimicrobials

Summary Table: Sources of Common Antibiotics