Chapter 10 Notes

Controlling Microbial Growth in the Body: Antimicrobial Drugs

History of Antimicrobial Agents

The development of antimicrobial drugs revolutionized the treatment of infectious diseases. Key historical figures contributed to the discovery and advancement of these agents.

• Drugs: Chemicals that affect physiology in any manner.

• Chemotherapeutic agents: Drugs acting against diseases.

• Antimicrobial agents: Drugs that treat infections.

• Paul Ehrlich: Proposed "magic bullets"—arsenic compounds that kill microbes.

• Alexander Fleming: Discovered penicillin released from Penicillium.

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

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

• Semisynthetics: Chemically altered antibiotics for improved effectiveness, stability, and administration.

• Synthetics: Antimicrobials completely synthesized in a laboratory.

Mechanisms of Action of Antimicrobial Drugs

Antimicrobial drugs target pathogens through various mechanisms, aiming for selective toxicity—harming the pathogen while leaving host cells unharmed.

Inhibition of Cell Wall Synthesis

• Bacterial cell wall: Most agents prevent cross-linkage of NAM (N-acetylmuramic acid) subunits in peptidoglycan.

• Beta-lactams: Bind to enzymes that cross-link NAM subunits, weakening cell walls and causing lysis. Effective only for growing cells.

• Semisynthetic beta-lactams: More stable, better absorbed, less susceptible to deactivation, broader activity.

• Vancomycin & Cycloserine: Interfere with bridges linking NAM subunits in Gram-positive bacteria.

• Bacitracin: Blocks transport of NAG (N-acetylglucosamine) and NAM from cytoplasm.

• Isoniazid & Ethambutol: Disrupt mycolic acid formation in mycobacterial species.

Inhibition of Fungal Cell Wall Synthesis

• Fungal cell wall: Composed of polysaccharides not found in mammalian cells.

• Echinocandins: Inhibit enzymes that synthesize glucan, a key fungal cell wall component.

Inhibition of Protein Synthesis

• Prokaryotic ribosomes: 70S; eukaryotic ribosomes: 80S. Drugs can selectively target translation in prokaryotes.

• Mitochondria: Contain 70S ribosomes; some drugs may harm host cells.

• Mupirocin: Binds isoleucyl-tRNA synthetase, preventing loading of isoleucine onto tRNA in Gram-positive bacteria.

Disruption of Cytoplasmic Membrane

• Nystatin & Amphotericin B: Attach to ergosterol in fungal membranes, forming channels and damaging integrity.

• Azoles & Allylamines: Inhibit ergosterol synthesis.

• Polymyxin: Disrupts cytoplasmic membranes of Gram-negative bacteria; toxic to human kidneys.

Inhibition of Metabolic Pathways

• Antimetabolic agents: Effective when pathogen and host metabolic processes differ.

• Atovaquone: Interferes with electron transport in protozoa and fungi.

• Heavy metals: Inactivate enzymes.

• Trimethoprim: Interferes with nucleotide synthesis.

• Amantadine & Rimantadine: Prevent viral uncoating.

• Protease inhibitors: Block enzymes required for HIV replication.

Inhibition of Nucleic Acid Synthesis

• Quinolones & Fluoroquinolones: Act against prokaryotic DNA gyrase.

• Nucleotide/Nucleoside analogs: Distort nucleic acid shapes, preventing replication, transcription, or translation. Used against viruses and rapidly dividing cancer cells.

• Reverse transcriptase inhibitors: Target HIV enzyme; humans lack reverse transcriptase.

Prevention of Virus Attachment, Entry, or Uncoating

• Attachment antagonists: Block viral attachment or receptor proteins.

• Pleconaril: Blocks viral attachment.

• Arildone: Prevents viral uncoating.

Clinical Considerations in Prescribing Antimicrobial Drugs

Choosing the right antimicrobial agent involves evaluating its properties, spectrum, effectiveness, administration, and safety.

Ideal Antimicrobial Agents

• Readily available

• Inexpensive

• Chemically stable

• Easily administered

• Nontoxic and nonallergenic

• Selectively toxic against a wide range of pathogens

Spectrum of Action

• Narrow-spectrum: Effective against a few organisms.

• Broad-spectrum: Effective against many organisms; may lead to secondary infections and reduced microbial antagonism.

Effectiveness Testing

• Diffusion susceptibility test

• Minimum inhibitory concentration (MIC) test

• Minimum bactericidal concentration (MBC) test

Routes of Administration

• Topical application

• Oral route

• Intramuscular (IM): Delivers drug into muscle

• Intravenous (IV): Delivers drug into bloodstream

Safety and Side Effects

• Toxicity: May affect kidneys, liver, or nerves; therapeutic index is the ratio of tolerated dose to effective dose.

• Allergies: Rare but potentially life-threatening (e.g., anaphylactic shock).

• Disruption of normal microbiota: May result in secondary infections, especially in hospitalized patients.

Resistance to Antimicrobial Drugs

Microbial resistance is a growing concern, with pathogens developing mechanisms to evade antimicrobial agents.

Resistance and Persister Cells

• Some pathogens are naturally resistant.

• Resistance can be acquired via mutations or acquisition of R plasmids through transformation, transduction, or conjugation.

CDC Threat Levels for Microbial Resistance

Threat Level	Description
Urgent	Potential for widespread, life-threatening disease
Serious	Alternative agents available or disease incidence is low/declining
Concerning	Low threat or numerous antimicrobials available

Mechanisms of Resistance

• Produce enzyme that destroys or deactivates drug

• Slow or prevent entry of drug into the cell

• Alter target of drug so it binds less effectively

• Alter metabolic chemistry

• Pump antimicrobial drug out of cell before it can act

• Bacteria in biofilms can resist antimicrobials

• Example: Mycobacterium tuberculosis produces MfpA protein, binding DNA gyrase and preventing fluoroquinolone binding

Multiple Resistance and Cross Resistance

• Pathogens can acquire resistance to more than one drug, especially via R plasmid exchange.

• Multiple drug-resistant pathogens: Resistant to at least three antimicrobial agents.

• Cross resistance: Occurs when drugs are similar in structure.

Retarding Resistance

• Maintain high concentration of drug in patient for sufficient time.

• Inhibit pathogen so immune system can eliminate it.

• Synergism: One drug enhances the effect of another.

• Antagonism: Drugs interfere with each other.

• Second and third generation drugs: New variations developed to overcome resistance.

Key Terms and Concepts

• Selective toxicity: Ability of a drug to target pathogens without harming host cells.

• Therapeutic index: $\frac{\text{Tolerated dose}}{\text{Effective dose}}$

• Minimum inhibitory concentration (MIC): Lowest concentration of drug that prevents visible growth.

• Minimum bactericidal concentration (MBC): Lowest concentration of drug that kills bacteria.

Example Applications

• Penicillin: Used to treat Gram-positive bacterial infections by inhibiting cell wall synthesis.

• Trimethoprim: Used in combination with sulfamethoxazole to treat urinary tract infections by inhibiting folic acid synthesis.

• Protease inhibitors: Used in antiretroviral therapy for HIV.