Antimicrobial Drugs: Mechanisms, Classes, and Resistance

Antimicrobial Drugs

Introduction to Antimicrobial Drugs

Antimicrobial drugs are chemical substances designed to destroy pathogenic microorganisms with minimal harm to host tissues. These agents are a cornerstone of modern medicine, enabling the treatment of infectious diseases caused by bacteria, fungi, protozoa, helminths, and viruses.

• Antimicrobial drug: A chemical that kills or inhibits the growth of microorganisms.

• Chemotherapeutic agents: Chemicals used to treat disease within the body, including antimicrobial drugs.

The History of Chemotherapy

Development of Antimicrobial Therapy

• Paul Ehrlich introduced the concept of chemotherapy for microbial diseases.

• Sulfa drugs became prominent in the 1930s as some of the first effective chemotherapeutic agents.

• Penicillin was discovered by Alexander Fleming in 1928; clinical trials began in 1940.

• Most antibiotics are produced by Streptomyces bacteria.

The Spectrum of Antimicrobial Activity

Range and Selectivity of Antimicrobial Drugs

• Antibacterial drugs target various structures and processes in prokaryotic cells.

• Fungal, protozoan, and helminthic infections are harder to treat due to their eukaryotic cell structure, which is more similar to human cells.

• Narrow-spectrum drugs affect a limited group of microbes (e.g., only gram-positive bacteria).

• Broad-spectrum drugs affect a wide variety of microbes.

• Small, hydrophilic drugs can penetrate and affect gram-negative bacteria.

• Antimicrobial agents should minimize harm to normal microbiota.

• Superinfections occur when drug-resistant pathogens or normally resistant microbiota proliferate excessively.

Action of Antimicrobial Drugs

Mechanisms of Action

• Drugs may be bactericidal (kill bacteria) or bacteriostatic (inhibit growth).

• Inhibition of cell wall synthesis (e.g., penicillins).

• Inhibition of protein synthesis (e.g., chloramphenicol, tetracyclines, streptomycin) by targeting 70S ribosomes.

• Disruption of plasma membranes (e.g., ionophore and polypeptide antibiotics).

• Inhibition of nucleic acid synthesis.

• Competitive inhibition of essential metabolites (e.g., sulfanilamide).

Common Antimicrobial Drugs

Antibacterial Antibiotics: Inhibitors of Cell Wall Synthesis

• All penicillins contain a β-lactam ring.

• Natural penicillins (from Penicillium) are effective against gram-positive cocci and spirochetes.

• Penicillinases (β-lactamases) are bacterial enzymes that destroy natural penicillins.

• Semisynthetic penicillins are resistant to penicillinases and have a broader spectrum.

• Carbapenems are broad-spectrum antibiotics inhibiting cell wall synthesis.

• Monobactam (aztreonam) targets only gram-negative bacteria.

• Cephalosporins inhibit cell wall synthesis and are used against penicillin-resistant strains.

• Bacitracin (a polypeptide) inhibits cell wall synthesis in gram-positive bacteria.

• Vancomycin is used against penicillinase-producing staphylococci.

• Isoniazid (INH) and ethambutol inhibit cell wall synthesis in mycobacteria.

Inhibitors of Protein Synthesis

• Drugs such as chloramphenicol, aminoglycosides, tetracyclines, glycylcyclines, macrolides, streptogramins, oxazolidinones, and pleuromutilins inhibit protein synthesis at 70S ribosomes.

Injury to Membranes

• Lipopeptides (e.g., polymyxin B) and bacitracin damage plasma membranes.

Nucleic Acid Synthesis Inhibitors

• Rifamycin inhibits mRNA synthesis; used for tuberculosis.

• Quinolones and fluoroquinolones inhibit DNA gyrase.

Competitive Inhibitors of Essential Metabolites

• Sulfonamides inhibit folic acid synthesis.

• SMZ-TMP inhibits dihydrofolic acid synthesis.

Antifungal Drugs

• Polyenes (e.g., nystatin, amphotericin B) bind to membrane sterols and are fungicidal.

• Azoles and allylamines interfere with sterol synthesis; used for mycoses.

• Echinocandins inhibit fungal cell wall synthesis.

• Flucytosine is a cytosine antimetabolite.

• Griseofulvin interferes with eukaryotic cell division; treats skin fungal infections.

Antiviral Drugs

• Entry and fusion inhibitors block viral attachment and entry.

• Nucleoside/nucleotide analogs (e.g., acyclovir, zidovudine) inhibit viral DNA/RNA synthesis.

• Viral enzyme inhibitors prevent viral assembly and release.

• Alpha interferons inhibit viral spread to new cells.

Antiprotozoan and Antihelminthic Drugs

• Antiprotozoan drugs: chloroquine, artemisinin, quinacrine, diiodohydroxyquin, pentamidine, metronidazole.

• Antihelminthic drugs: mebendazole, praziquantel, ivermectin.

Tests to Guide Chemotherapy

Determining Drug Effectiveness

• Tests identify the most effective chemotherapeutic agent for a specific pathogen, especially when resistance is suspected.

Diffusion Methods

• Disk-diffusion (Kirby-Bauer) test: Bacterial culture is inoculated on agar; disks with drugs are placed on the surface. After incubation, the zone of inhibition is measured to determine sensitivity.

• Minimal inhibitory concentration (MIC): The lowest drug concentration preventing visible growth; estimated with the E test.

Broth Dilution Tests

• Microorganisms are grown in liquid media with varying drug concentrations.

• Minimum bactericidal concentration (MBC): The lowest concentration that kills bacteria.

Resistance to Antimicrobial Drugs

Mechanisms and Spread of Resistance

• Many bacterial diseases have become resistant to antibiotics.

• Superbugs: Bacteria resistant to multiple antibiotics.

• Resistance genes can be transferred horizontally between bacteria.

• Mechanisms of resistance include:

  • Enzymatic destruction of the drug

  • Prevention of drug penetration

  • Alteration of drug target site

  • Rapid efflux (pumping out) of the antibiotic

  • Metabolic pathway changes

• Appropriate use of drugs in correct concentrations and dosages can minimize resistance.

Antibiotic Safety

Risk-Benefit Analysis

• Potential risks (side effects) must be weighed against benefits (curing infection) before using antibiotics.

Effects of Drug Combinations

Synergism and Antagonism

• Synergistic combinations: Drugs are more effective together than alone.

• Antagonistic combinations: Drugs are less effective together than alone.

Future of Antimicrobial Agents

New Approaches and Agents

• New agents include antimicrobial peptides, bacteriocins, and bacteriophages.

• Targeting virulence factors (rather than cell growth) is a promising strategy.

Summary Table: Major Classes of Antimicrobial Drugs

Drug Class	Main Target	Examples	Notes
β-lactams	Cell wall synthesis	Penicillins, cephalosporins, carbapenems	Contain β-lactam ring; resistance via β-lactamases
Glycopeptides	Cell wall synthesis	Vancomycin	Used for resistant gram-positive bacteria
Aminoglycosides	Protein synthesis (30S ribosome)	Streptomycin, gentamicin	Bactericidal; nephrotoxic
Macrolides	Protein synthesis (50S ribosome)	Erythromycin, azithromycin	Alternative to penicillins
Polypeptides	Cell membrane	Bacitracin, polymyxin B	Topical use
Quinolones/Fluoroquinolones	DNA gyrase	Ciprofloxacin	Broad-spectrum
Sulfonamides	Folic acid synthesis	Sulfamethoxazole	Often combined with trimethoprim
Polyenes	Fungal membrane sterols	Amphotericin B, nystatin	Fungicidal
Azoles	Fungal sterol synthesis	Fluconazole, ketoconazole	Used for mycoses
Antivirals	Viral enzymes, entry, or nucleic acid synthesis	Acyclovir, zidovudine	Used for herpes, HIV, etc.

Key Equations

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

• Minimum Bactericidal Concentration (MBC): The lowest concentration of an antimicrobial that kills 99.9% of the initial bacterial population.

$\text{MIC} = \min \{ C : \text{no visible growth at concentration } C \}$

$\text{MBC} = \min \{ C : \text{no viable bacteria recovered at concentration } C \}$

Example: Kirby-Bauer Disk Diffusion Test

• A plate is inoculated with a bacterial lawn.

• Disks containing antibiotics are placed on the surface.

• After incubation, clear zones (zones of inhibition) indicate effectiveness.

• The diameter of the zone is compared to standards to classify the organism as sensitive, intermediate, or resistant.

Additional info:

• Antimicrobial stewardship is critical to prevent the spread of resistance.

• Combination therapy can reduce the likelihood of resistance development.