Antimicrobial Drugs: History, Mechanisms, and Resistance

History and Principles of Chemotherapy

Development of Chemotherapy

Chemotherapy refers to the use of chemicals to treat diseases, particularly infections caused by microorganisms. The concept of selective toxicity, introduced by Paul Ehrlich in the early 1900s, is fundamental: drugs should target pathogens without harming the host.

• Selective Toxicity: The ability of a drug to target microbial cells without damaging host cells.

• Magic Bullet: Ehrlich's idea of a chemical that selectively targets pathogens.

• Antibiotic: A substance produced by a microbe that inhibits the growth of another microbe.

• Antimicrobial Drugs: Synthetic substances that interfere with microbial growth.

Discovery of Penicillin

Alexander Fleming discovered penicillin in 1928, marking the beginning of the antibiotic era. Penicillin was first clinically tested in 1940.

• Penicillin: The first widely used antibiotic, effective against many bacterial infections.

Representative Sources of Antibiotics

Antibiotics are produced by various microorganisms, including bacteria, actinomycetes, and fungi.

Microorganism	Antibiotic
Gram-Positive Rods	Bacitracin, Polymyxin
Actinomycetes	Streptomyces (various antibiotics), Micromonospora (Gentamicin)
Fungi	Cephalosporin, Griseofulvin, Penicillin

Spectrum of Antimicrobial Activity

Broad vs. Narrow Spectrum

The spectrum of activity describes the range of microorganisms an antimicrobial drug can affect.

• Broad-spectrum antibiotics: Effective against a wide variety of microbes.

• Narrow-spectrum antibiotics: Target specific groups of bacteria.

Drug	Effective Against
Penicillin G	Gram-positive bacteria
Tetracycline	Gram-positive, Gram-negative, Chlamydias, Rickettsias
Acyclovir	Viruses

Mechanisms of Action of Antimicrobial Drugs

Major Mechanisms

Antimicrobial drugs act through several mechanisms:

• Inhibition of cell wall synthesis: Penicillins, cephalosporins, bacitracin, vancomycin

• Inhibition of protein synthesis: Chloramphenicol, erythromycin, tetracyclines, streptomycin

• Inhibition of nucleic acid replication and transcription: Quinolones, rifampin

• Injury to plasma membrane: Polymyxin B

• Inhibition of essential metabolite synthesis: Sulfanilamide, trimethoprim

Antibacterial Antibiotics: Inhibitors of Cell Wall Synthesis

Penicillins

Penicillins contain a β-lactam ring and prevent cross-linking of peptidoglycans, interfering with cell wall construction, especially in gram-positive bacteria.

• Natural Penicillins: Penicillin G (injection), Penicillin V (oral)

• Semisynthetic Penicillins: Modified to resist penicillinase or broaden spectrum (e.g., oxacillin, ampicillin)

• Penicillinase-resistant penicillins: Methicillin, oxacillin

• Extended-spectrum penicillins: Effective against gram-negatives and gram-positives

• Penicillins plus β-lactamase inhibitors: Combine with clavulanic acid to inhibit penicillinase

Cephalosporins

Cephalosporins are structurally similar to penicillins but have a different β-lactam ring. They are grouped by generations based on their spectrum and resistance to β-lactamase.

Polypeptide Antibiotics

• Bacitracin: Topical application; effective against gram-positives

• Vancomycin: Glycopeptide; last line against MRSA

• Teixobactin: New class; effective against gram-positives

Competitive Inhibition of Essential Metabolites

Sulfonamides

Sulfonamides inhibit folic acid synthesis, which is essential for nucleic acid and protein synthesis. They competitively bind to the enzyme that normally binds PABA, a folic acid precursor.

• Drug Synergism: Combination of trimethoprim and sulfamethoxazole (TMP-SMZ) increases efficacy.

Antifungal and Antiviral Drugs

Antifungal Drugs

Antifungal drugs target fungal sterols, cell walls, nucleic acids, or microtubule assembly.

• Ergosterol synthesis inhibitors: Disrupt membrane permeability

• β-glucan inhibitors: Target fungal cell wall

• Flucytosine: Cytosine analog interferes with RNA synthesis

• Microtubule inhibitors: Block cell division

Antiviral Drugs

Antiviral drugs act by blocking entry, fusion, uncoating, genome integration, nucleic acid synthesis, assembly, and exit.

• Entry and fusion inhibitors: Block virus binding or fusion

• Nucleoside analogs: Inhibit viral RNA or DNA synthesis

• Protease and neuraminidase inhibitors: Block viral assembly and release

• Interferons: Induce antiviral proteins in host cells

Tests to Guide Chemotherapy

Disk-Diffusion Method (Kirby-Bauer Test)

Paper disks with chemotherapeutic agents are placed on agar containing the test organism. The zone of inhibition determines sensitivity.

E Test

Determines the minimal inhibitory concentration (MIC), the lowest antibiotic concentration preventing bacterial growth.

Broth Dilution Tests

Used to determine MIC and minimal bactericidal concentration (MBC) of an antimicrobial drug.

Resistance to Antimicrobial Drugs

Mechanisms of Resistance

Bacteria can develop resistance through various mechanisms:

• Persister cells: Survive antibiotic exposure due to genetic traits

• Superbugs: Resistant to multiple antibiotics

• Horizontal gene transfer: Resistance genes spread via plasmids or transposons

Antibiotic Misuse

Misuse of antibiotics selects for resistance mutants. Common misuse includes:

• Using outdated or weakened antibiotics

• Using antibiotics for viral infections

• Using antibiotics in animal feed

• Failing to complete prescribed regimen

• Using someone else's prescription

Effects of Combinations of Drugs

Synergism and Antagonism

• Synergism: The effect of two drugs together is greater than either alone.

• Antagonism: The effect of two drugs together is less than either alone.

Future of Chemotherapeutic Agents

Emerging Strategies

• Targeting virulence factors: Disrupting pathogen mechanisms without killing them

• Sequestering iron: Limiting pathogen access to essential nutrients

• Antimicrobial peptides: Produced by various organisms, including bacteriocins from bacteria

• Phage therapy: Using bacteriophages to target bacterial infections