Chapter 20: Antimicrobial Drugs – Comprehensive Study Notes

Antimicrobial Drugs

Introduction

Antimicrobial drugs are agents used to treat infections by inhibiting or killing microorganisms. Their development and use are central to modern medicine, especially in the treatment of bacterial, fungal, protozoal, and viral diseases. Understanding their mechanisms, spectrum, and resistance is crucial for effective therapy.

Student Learning Objectives

• Learn about the spectrum of antimicrobial activity for different chemotherapeutic drugs.

• Differentiate among the different modes of action of antibacterial drugs.

• Understand the concept of susceptibility and describe tests for microbial susceptibility to chemotherapeutic agents.

• Understand the concept of microbial resistance to antimicrobial medicines.

• Understand the different mechanisms by which bacteria become resistant to chemotherapeutic agents.

Spectrum of Antimicrobial Activity

Narrow vs. Broad Spectrum

• Narrow-spectrum antibiotics: Active against a limited variety of bacteria. Example: Penicillin G (mainly gram-positive bacteria).

• Broad-spectrum antibiotics: Affect a wide range of gram-positive and gram-negative bacteria. Examples:

  • Tetracycline: Acts against gram-negative, gram-positive, mycobacterium, and intracellular bacteria (chlamydia, rickettsia).

  • Streptomycin: Acts against mycobacterium, gram-negative, and some gram-positive bacteria.

Cellular Targets and Selective Toxicity

Prokaryotic vs. Eukaryotic Cells

• Selective toxicity is essential: drugs must target the microorganism, not the host.

• Some antibiotics that inhibit protein synthesis in bacteria may also affect mitochondrial ribosomes in eukaryotic cells due to their similarity (both are 70S ribosomes).

• Non-specificity of therapeutic drugs can lead to side effects if drugs target structures common to both pathogens and host cells.

Key Differences Between Prokaryotic and Eukaryotic Cells

Characteristic	Prokaryotic	Eukaryotic
Size	0.2–2.0 μm	10–100 μm
Nucleus	Absent	Present
Membrane-bound organelles	Absent	Present
Cell wall	Peptidoglycan (bacteria)	Cellulose (plants), chitin (fungi), none (animals)
Ribosomes	70S	80S (cytoplasm), 70S (mitochondria)

Basic Sites of Antibiotic Action

• Cell wall synthesis: β-lactams (penicillins, cephalosporins), vancomycin, bacitracin

• Protein synthesis: Aminoglycosides, tetracyclines, macrolides, chloramphenicol

• Nucleic acid synthesis: Quinolones, rifampin

• Plasma membrane: Polymyxins

• Metabolite synthesis: Sulfonamides, trimethoprim

Mechanisms of Action of Antibacterial Drugs

1. Inhibition of Cell Wall Synthesis

• Penicillins, cephalosporins, carbapenems, monobactams: Prevent peptidoglycan synthesis, causing cell lysis.

• Selective toxicity: Human cells lack peptidoglycan.

Equation: $\text{Peptidoglycan synthesis} \xrightarrow{\text{inhibited}} \text{Cell wall weakened} \rightarrow \text{Cell lysis}$ Example: Penicillin is effective against actively growing gram-positive bacteria.

2. Inhibition of Protein Synthesis

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

• Tetracyclines: Block attachment of tRNA to the ribosome.

• Macrolides (erythromycin): Bind 50S subunit, inhibit translocation.

• Chloramphenicol: Inhibits peptide bond formation on 50S subunit.

Equation: $\text{Antibiotic} + \text{Ribosome} \rightarrow \text{Inhibition of protein synthesis}$ Example: Streptomycin is used for tuberculosis; erythromycin for respiratory infections.

3. Inhibition of Nucleic Acid Replication and Transcription

• Quinolones: Inhibit DNA gyrase (topoisomerase), blocking DNA replication.

• Rifampin: Inhibits RNA polymerase, blocking transcription.

Equation: $\text{DNA gyrase} + \text{Quinolone} \rightarrow \text{No DNA replication}$ Example: Ciprofloxacin for urinary tract infections; rifampin for tuberculosis.

4. Injury to Plasma Membrane

• Polymyxin B: Disrupts membrane integrity, causing leakage of cell contents.

Example: Polymyxin B is used topically for gram-negative infections.

5. Inhibition of Essential Metabolite Synthesis (Antimetabolites)

• Sulfonamides: Competitive inhibitors of para-aminobenzoic acid (PABA), blocking folic acid synthesis.

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

Equation: $\text{Sulfonamide} + \text{Enzyme} \rightarrow \text{No folic acid} \rightarrow \text{No DNA/RNA synthesis}$ Example: Sulfamethoxazole-trimethoprim for urinary tract infections.

Antimicrobial Drugs for Eukaryotic Pathogens

Antifungal, Antiprotozoan, Antihelminthic, and Antiviral Drugs

• Antifungals: Target ergosterol in fungal membranes (e.g., ketoconazole, amphotericin B).

• Antiprotozoals: Target metabolic pathways (e.g., mefloquine for malaria).

• Antihelminthics: Disrupt energy metabolism (e.g., praziquantel for flukes, niclosamide for tapeworms).

• Antivirals: Inhibit viral replication (e.g., acyclovir for herpesviruses).

Advantages of Using Antibiotic Combinations

• Broaden the antibacterial spectrum for empirical therapy or polymicrobial infections.

• Prevent emergence of resistant organisms during therapy.

• Antibiotic synergism: Enhanced effect when two antibiotics are combined.

• Antibiotic antagonism: One antibiotic interferes with the activity of another.

Susceptibility and Resistance Testing

Definitions

• Susceptibility: Microorganism is inhibited or killed by an antimicrobial agent.

• Resistance: Microorganism can grow in the presence of an antimicrobial agent.

Testing Methods

• Disk-diffusion (Kirby-Bauer) test: Zone of inhibition around antibiotic disk indicates susceptibility.

• Broth dilution test: Determines minimum inhibitory concentration (MIC).

Mechanisms of Bacterial Resistance

• Enzymatic destruction or inactivation of the drug (e.g., β-lactamase production).

• Prevention of drug penetration (e.g., altered porins in gram-negative bacteria).

• Alteration of drug's target site (e.g., altered penicillin-binding proteins in MRSA).

• Rapid efflux (ejection) of the antibiotic.

Example: Methicillin-resistant Staphylococcus aureus (MRSA) produces altered penicillin-binding proteins encoded by the mecA gene.

Plasmids and Resistance

• Plasmids: Small, circular DNA molecules carrying resistance genes (R factors).

• Can be transferred between bacteria via conjugation, spreading resistance.

Disinfectants and Antimicrobial Chemicals

• Aldehydes (formaldehyde, glutaraldehyde): Inactivate proteins, used for disinfection and sterilization.

• Peroxygens (hydrogen peroxide, peracetic acid): Oxidizing agents, effective against a broad range of microbes, including spores.

Probiotics

• Live non-pathogenic bacteria and yeast used for prevention and treatment of infections.

• Compete with pathogens for binding sites and reduce inflammation.

• Examples: Lactobacillus rhamnosus, Saccharomyces boulardii.

Antimicrobial Drugs: Summary Tables

Summary of Antibiotics by Mode of Action

Drug Class	Mode of Action	Example
β-lactams	Inhibit cell wall synthesis	Penicillin, cephalosporin
Aminoglycosides	Inhibit protein synthesis (30S)	Streptomycin
Macrolides	Inhibit protein synthesis (50S)	Erythromycin
Quinolones	Inhibit DNA replication	Ciprofloxacin
Polymyxins	Disrupt plasma membrane	Polymyxin B
Sulfonamides	Inhibit folic acid synthesis	Sulfamethoxazole

Summary of Antifungal, Antiprotozoan, and Antihelminthic Drugs

Drug	Target	Example
Polyenes	Fungal membrane sterols	Amphotericin B
Azoles	Ergosterol synthesis	Ketoconazole
Antiprotozoals	Metabolic pathways	Mefloquine (malaria)
Antihelminthics	Energy metabolism	Praziquantel (flukes)

Genetic History and Malaria

• Heterozygous advantage: Individuals with sickle cell trait are protected from malaria.

• Glucose-6-phosphate dehydrogenase (G6PD) deficiency also confers protection against severe malaria.

References

• Tortora, G. J., et al. (2019). Microbiology: An Introduction, 13th Edition. Pearson Education, Inc.