Controlling Microbial Growth in the Body: Antimicrobial Drugs

The History and Classification of Antimicrobial Agents

Antimicrobial drugs are chemicals used to treat infections by inhibiting or killing pathogenic microorganisms. The development of these agents revolutionized medicine, allowing for the effective treatment of bacterial, fungal, and some viral diseases.

• Drugs: Chemicals that affect physiology in any manner.

• Chemotherapeutic agents: Drugs that act against diseases.

• Antimicrobial agents (antimicrobials): Drugs that treat infections.

• Goal of antimicrobial chemotherapy: Destroy the infective agent without harming the host’s cells.

• Key historical figures:

  • Paul Ehrlich: Introduced the concept of "magic bullets" and chemotherapy.

  • Alexander Fleming: Discovered penicillin from Penicillium fungus.

  • Gerhard Domagk: Discovered sulfanilamide, the first widely available antimicrobial.

  • Selman Waksman: Coined the term "antibiotics" for naturally produced antimicrobial agents.

• Semi-synthetics: Chemically altered natural antibiotics with improved properties.

• Synthetics: Completely synthesized antimicrobials in the laboratory.

Mechanisms of Antimicrobial Action

Antimicrobial drugs target specific structures or functions in microbes that are distinct from those in the host, ensuring selective toxicity. The main mechanisms include inhibition of cell wall synthesis, protein synthesis, nucleic acid synthesis, metabolic pathways, and disruption of cytoplasmic membranes.

• Selective toxicity: Drugs exploit differences between host and pathogen.

• Antibacterial drugs: Most numerous due to unique bacterial targets.

• Antifungal, antiprotozoal, and antiviral drugs: Fewer due to similarities with host cells.

Inhibition of Bacterial Cell Wall Synthesis

Many antibiotics, especially beta-lactams, inhibit the synthesis of peptidoglycan, a key component of bacterial cell walls. This leads to weakened cell walls and eventual lysis due to osmotic pressure.

• Beta-lactams: Bind to enzymes that cross-link NAM subunits, preventing cell wall formation (e.g., penicillins, cephalosporins, carbapenems).

• Semi-synthetic derivatives: More stable, better absorbed, broader spectrum.

• Other agents: Vancomycin and cycloserine disrupt bridges in Gram-positive bacteria; bacitracin blocks transport of NAG and NAM; isoniazid and ethambutol disrupt mycolic acid in mycobacteria.

Inhibition of Fungal Cell Wall Synthesis

Fungal cell walls contain unique polysaccharides. Echinocandins, such as caspofungin, inhibit glucan synthesis, leading to cell wall rupture.

• Echinocandins: Inhibit glucan synthesis in fungi.

• Example: Caspofungin.

Inhibition of Protein Synthesis

Antibiotics can target bacterial ribosomes (70S), which differ from eukaryotic ribosomes (80S). This allows selective inhibition of bacterial protein synthesis.

• Examples: Aminoglycosides (e.g., gentamicin), tetracyclines, macrolides, and oxazolidinones.

• Special cases: Mupirocin inhibits isoleucyl-tRNA synthetase; oxazolidinones prevent 70S ribosome formation.

• Note: Mitochondria in eukaryotes have 70S ribosomes, so some toxicity may occur.

Disruption of Cytoplasmic Membranes

Some drugs disrupt the integrity of microbial membranes, causing cell death. These drugs often target sterols unique to fungi or specific lipids in bacteria.

• Polyenes (e.g., amphotericin B, nystatin): Bind to ergosterol in fungal membranes, forming pores.

• Azoles and allylamines: Inhibit ergosterol synthesis in fungi.

• Polymyxin: Disrupts Gram-negative bacterial membranes; nephrotoxic, used topically.

Inhibition of Metabolic Pathways

Some antimicrobials act as metabolic antagonists, interfering with pathways unique to microbes. Sulfonamides and trimethoprim are classic examples, blocking folic acid synthesis in bacteria and protozoa.

• Sulfonamides: Structural analogs of PABA, inhibit dihydrofolic acid synthesis.

• Trimethoprim: Inhibits a later step in folic acid synthesis.

• Other agents: Atovaquone (electron transport), heavy metals (enzyme inactivation), antiviral drugs (block viral uncoating or protease activity).

Inhibition of Nucleic Acid Synthesis

Some drugs block DNA replication or RNA transcription. These are often used against viruses or in research due to their toxicity to host cells.

• Quinolones/fluoroquinolones: Inhibit DNA gyrase in bacteria.

• Nucleotide/nucleoside analogs: Mimic DNA/RNA building blocks, causing chain termination (e.g., AZT, acyclovir).

• Reverse transcriptase inhibitors: Block HIV replication; selective for viral enzymes.

Prevention of Virus Attachment, Entry, or Uncoating

Some antiviral drugs prevent viruses from attaching to or entering host cells, or from uncoating once inside.

• Attachment antagonists: Block viral proteins or host receptors (e.g., pleconaril).

• Uncoating inhibitors: Prevent viral genome release (e.g., arildone).

Clinical Considerations in Prescribing Antimicrobial Drugs

Choosing the right antimicrobial involves considering its spectrum of action, effectiveness, route of administration, safety, and potential for resistance.

• Spectrum of action: Narrow-spectrum drugs target specific pathogens; broad-spectrum drugs affect many types but may disrupt normal flora and cause superinfections.

Testing for Drug Susceptibility

• Kirby-Bauer (disk diffusion) test: Measures zones of inhibition to determine susceptibility.

• Minimum inhibitory concentration (MIC): Lowest concentration that inhibits visible growth.

• Minimum bactericidal concentration (MBC): Lowest concentration that kills the organism.

Routes of Administration

• Topical: For external infections.

• Oral: Convenient, but variable absorption.

• Intramuscular (IM): Injection into muscle.

• Intravenous (IV): Direct to bloodstream, highest concentration.

Safety and Side Effects

• Toxicity: May affect kidneys, liver, nerves; tetracyclines can discolor teeth and harm fetal development.

• Allergies: Rare but can cause anaphylactic shock.

• Disruption of normal microbiota: May lead to secondary infections or superinfections, especially in hospitalized patients.

Therapeutic Index (TI) and Therapeutic Window

• Therapeutic index (TI):

• Higher TI values are safer. A TI of 10 is safer than a TI of 1.1.

• Therapeutic window: Range of concentrations where the drug is effective but not toxic.

Development of Resistance in Populations

Bacteria can develop resistance through mutations or acquiring resistance genes via horizontal gene transfer. Resistance mechanisms include drug inactivation, altered targets, reduced entry, efflux pumps, and biofilm formation.

• Beta-lactamases: Enzymes that destroy beta-lactam antibiotics.

• Multiple drug resistance (MDR): Pathogens resistant to three or more drugs.

• Cross-resistance: Resistance to similar drugs due to shared mechanisms.

Strategies to Slow Resistance

• Use antimicrobials only when necessary.

• Maintain high drug concentrations for sufficient time.

• Use combinations of drugs (synergism).

• Develop new drugs and modify existing ones.

• Design drugs to target unique microbial proteins.