Ch 10 lecture

Controlling Microbial Growth in the Body

Week 7 Overview

This week's materials focus on the principles of antimicrobial agents, their mechanisms of action, and the growing problem of drug resistance in microbes. Understanding these concepts is essential for effective treatment of infectious diseases and for combating the rise of antibiotic-resistant pathogens.

Learning Objectives

• Name the different mechanisms of antibiotic resistance.

• Describe different mechanisms of action for antibiotics.

• Explain how to test the efficacy of antimicrobial drugs.

Antimicrobial Agents

Definition and Types

Antimicrobial agents are substances that affect the physiology of an organism, often by inhibiting or killing microbes. They include a wide range of compounds, from common chemicals (caffeine, alcohol, nicotine) to specialized drugs used in medicine.

• Therapeutics: Drugs that act against a disease (e.g., statins for cholesterol, Nexium for acid reflux).

• Antimicrobial agents: Drugs that treat infections by either killing or inhibiting the growth of microbes.

History of Antimicrobial Agents

• Paul Ehrlich: Coined the term chemotherapy for drugs that selectively kill pathogens.

• Salvarsan: An arsenic compound effective against microbes, representing early targeted therapy.

• Prontosil (sulfanilamide): The first commercially available antibacterial drug, leading to the development of sulfa drugs.

• Penicillin: Discovered by Alexander Fleming, later developed by Florey and Chain; revolutionized bacterial infection treatment.

Types of Antimicrobial Agents

• Antibiotics: Naturally produced by microorganisms to kill or inhibit other microbes.

• Synthetic drugs: Fully synthesized in the laboratory.

• Semisynthetic drugs: Chemically modified antibiotics to improve efficacy or reduce side effects.

Mechanisms of Action of Antimicrobial Drugs

Selective Toxicity

The ideal antimicrobial agent targets microbial processes or structures not found in the host, minimizing harm to human cells.

Main Mechanisms

• Inhibition of Cell Wall Synthesis: Drugs like penicillins and cephalosporins prevent cross-linking of peptidoglycan (NAM-NAG chains), leading to cell lysis. Most effective against actively growing bacteria.

• Disruption of Cell Membrane: Agents such as polymyxins (bacterial) and amphotericin B (fungal) form channels in membranes, compromising integrity. Fungal drugs target ergosterol, a component absent in human cells.

• Inhibition of Protein Synthesis: Many antibiotics (e.g., tetracyclines, macrolides) target bacterial ribosomes (70S), which differ from eukaryotic ribosomes (80S), allowing selective inhibition.

• Inhibition of Nucleic Acid Synthesis: Drugs like quinolones and rifampicin block DNA replication or RNA transcription, affecting both prokaryotes and, less commonly, eukaryotes.

• Inhibition of Metabolic Pathways: Sulfa drugs inhibit folic acid synthesis, a pathway present in bacteria but not in humans (who obtain folic acid from diet).

Drug Resistance

Definition and Importance

Drug resistance occurs when microbes evolve mechanisms to withstand the effects of antimicrobial agents. This leads to the re-emergence of diseases that were previously treatable and poses a major public health threat.

Mechanisms of Drug Resistance

• Enzymatic degradation: Microbes produce enzymes (e.g., beta-lactamases) that destroy antibiotics.

• Alteration of target proteins: Mutations change the drug's binding site, reducing efficacy.

• Efflux pumps: Proteins actively pump drugs out of the cell, lowering intracellular concentrations.

• Changes in membrane permeability: Prevent drug entry into the cell.

Development and Spread of Resistance

• Resistance can arise from mutations in chromosomal genes or acquisition of resistance genes via plasmids (R-plasmids) through transformation, transduction, or conjugation.

• Cross-resistance occurs when a single resistance mechanism confers resistance to multiple drugs, especially within the same class.

Clinical Impact

Antibiotic resistance leads to increased morbidity, mortality, and healthcare costs. "Superbugs" like MRSA (Methicillin-resistant Staphylococcus aureus) are examples of pathogens with high resistance levels.

Testing Efficacy of Antimicrobial Drugs

Laboratory Methods

• Kirby-Bauer Disk Diffusion Test: Measures zones of inhibition around antibiotic disks on a bacterial lawn.

• Broth Dilution Test: Determines minimum inhibitory concentration (MIC) by observing bacterial growth in tubes with varying drug concentrations.

• E-test: Uses a gradient of antibiotic concentration on a strip to determine MIC directly on an agar plate.

Clinical Considerations in Prescribing Antimicrobials

• Route of administration: Oral, topical, intramuscular, or intravenous, depending on drug properties and infection site.

• Adverse effects: Toxicity to organs, allergic reactions, and disruption of normal flora (leading to secondary infections).

• Spectrum of action: Narrow-spectrum drugs target specific pathogens; broad-spectrum drugs affect a wide range, but may disrupt normal flora.

Summary Table: Mechanisms of Drug Resistance

Mechanism	Description	Example
Enzymatic degradation	Production of enzymes that destroy the drug	Beta-lactamase inactivating penicillin
Alteration of target	Mutation or modification of drug target site	Altered ribosomal proteins
Efflux pumps	Active transport of drug out of the cell	Tetracycline efflux pumps
Reduced permeability	Changes in membrane proteins prevent drug entry	Porin mutations in Gram-negative bacteria

Why Should We Care?

Antibiotic resistance is a global health crisis, threatening the effectiveness of current treatments and leading to increased deaths and healthcare costs. Monitoring, stewardship, and development of new drugs are essential to combat resistance.

Key Equations and Concepts

• Minimum Inhibitory Concentration (MIC): The lowest concentration of an antimicrobial that prevents visible growth of a microorganism.

• Selective toxicity: The ability of a drug to target microbial cells without harming host cells.

Example

A toddler with an ear infection may be prescribed Drug A (less effective, oral, $100, fewer side effects) or Drug B (more effective, injectable, more side effects). The choice depends on efficacy, safety, cost, and ease of administration.

Additional info:

• Superinfections can occur when broad-spectrum antibiotics kill normal flora, allowing opportunistic pathogens to proliferate.

• Antibiotic stewardship (using drugs only when necessary and completing the full course) is critical to limit resistance.