Antimicrobial Drugs: Mechanisms, Classes, and Resistance

Antimicrobial Drugs

Introduction to Antimicrobial Drugs

Antimicrobial drugs are essential tools in the treatment of infectious diseases. They include antibiotics (produced by microorganisms), synthetic drugs, and semi-synthetic derivatives. Their effectiveness is based on selective toxicity, which allows them to target pathogens without harming the host.

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

• Chemotherapy: The use of chemicals to treat disease.

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

• Antimicrobial drugs: Synthetic substances that interfere with the growth of microbes.

History of Chemotherapy

• 1928: Alexander Fleming discovered penicillin, produced by Penicillium.

• 1932: Prontosil red dye (a sulfanilamide) used for streptococcal infections.

• 1940: First clinical trials of penicillin.

• Modern challenge: Growing problem of antibiotic resistance.

Sources of Antibiotics

Antibiotics are derived from various microorganisms, including bacteria (especially Streptomyces and Bacillus species) and fungi (Penicillium and Cephalosporium).

Microorganism	Antibiotic
Gram-Positive Rods	Bacitracin, Polymyxin
Actinomycetes	Amphotericin B, Chloramphenicol, Tetracyclines, Erythromycin, Neomycin, Streptomycin, Gentamicin
Fungi	Cephalothin, Griseofulvin, Penicillin

Spectrum and Modes of Action

Spectrum of Antimicrobial Activity

• Narrow-spectrum antibiotics: Affect a limited range of bacteria (e.g., only gram-positive bacteria).

• Broad-spectrum antibiotics: Affect a wide range of bacteria, including both gram-positive and gram-negative species.

• Superinfection: Overgrowth of resistant normal microbiota, such as Candida albicans or Clostridioides difficile.

Major Modes of Action

Antimicrobial drugs target essential microbial processes:

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

• Inhibition of protein synthesis (e.g., chloramphenicol, erythromycin, tetracyclines, streptomycin)

• Inhibition of nucleic acid replication and transcription (e.g., quinolones, rifampin)

• Injury to plasma membrane (e.g., polymyxin B)

• Inhibition of essential metabolite synthesis (e.g., sulfanilamide, trimethoprim)

Inhibitors of Cell Wall Synthesis

Penicillins

• Contain a β-lactam ring essential for activity.

• Prevent cross-linking of peptidoglycans, interfering with cell wall construction (especially in gram-positive bacteria).

• Natural penicillins: Penicillin G (injected), Penicillin V (oral); narrow spectrum, susceptible to penicillinases.

• Semisynthetic penicillins: Modified side chains for resistance to penicillinases and broader spectrum.

Other β-lactam Antibiotics

• Carbapenems: Broad spectrum; e.g., imipenem, doripenem.

• Monobactams: Single ring; effective against certain gram-negatives (e.g., aztreonam).

• Cephalosporins: Similar to penicillins but with a different β-lactam ring; grouped by generations.

Polypeptide and Antimycobacterial Antibiotics

• Bacitracin: Topical; effective against gram-positives.

• Vancomycin: Last line against MRSA; resistance is emerging (VRSA, VRE).

• Isoniazid and Ethambutol: Inhibit mycolic acid synthesis in mycobacteria (e.g., Mycobacterium tuberculosis).

Inhibitors of Protein Synthesis

Mechanisms and Examples

• Chloramphenicol: Inhibits peptide bond formation at the 50S subunit; broad spectrum; can cause aplastic anemia.

• Aminoglycosides: Change shape of 30S subunit; can cause auditory and kidney damage (e.g., streptomycin, neomycin, gentamicin).

• Tetracyclines: Interfere with tRNA attachment; broad spectrum; can cause superinfections.

• Macrolides: Contain a macrocyclic lactone ring; effective against gram-positives (e.g., erythromycin).

• Streptogramins, Oxazolidinones, Pleuromutilins: Used for resistant gram-positive infections.

Inhibitors of Nucleic Acid Synthesis

• Rifamycins (rifampin): Inhibit mRNA synthesis; used for tuberculosis.

• Quinolones and Fluoroquinolones: Inhibit DNA gyrase; broad spectrum (e.g., ciprofloxacin).

Inhibitors of Essential Metabolite Synthesis

• Sulfonamides: Inhibit folic acid synthesis by competing with PABA.

• Trimethoprim: Inhibits conversion of dihydrofolic acid to tetrahydrofolic acid.

• Drug synergism: Combination of trimethoprim and sulfamethoxazole (TMP-SMZ) is more effective than either alone.

Antifungal, Antiviral, Antiprotozoan, and Antihelminthic Drugs

Antifungal Drugs

• Agents affecting fungal sterols: Polyenes (nystatin, amphotericin B), azoles (clotrimazole, miconazole), allylamines (terbinafine).

• Agents affecting fungal cell walls: Echinocandins (caspofungin).

• Agents inhibiting nucleic acids: Flucytosine.

• Other: Griseofulvin (inhibits microtubules), tolnaftate, pentamidine.

Antiviral Drugs

• Entry and fusion inhibitors: Block viral entry into host cells.

• Uncoating, genome integration, and nucleic acid synthesis inhibitors: Prevent viral replication (e.g., acyclovir for herpesviruses).

• Assembly and exit inhibitors: Protease inhibitors (e.g., Paxlovid® for COVID-19), neuraminidase inhibitors (e.g., oseltamivir for influenza).

• Interferons: Produced by infected cells to inhibit viral spread.

• Antiretrovirals: Used to treat HIV/AIDS.

Antiprotozoan and Antihelminthic Drugs

• Antiprotozoan: Quinine, chloroquine, artemisinin (malaria); metronidazole (anaerobic bacteria and protozoa); miltefosine (leishmaniasis).

• Antihelminthic: Niclosamide (tapeworms), praziquantel (flukes), mebendazole/albendazole (intestinal helminths), ivermectin (roundworms and mites).

Testing Microbial Susceptibility

Diffusion Methods

• Disk-diffusion (Kirby-Bauer) test: Paper disks with antibiotics placed on inoculated agar; zone of inhibition indicates sensitivity.

• E test: Determines minimal inhibitory concentration (MIC) using a gradient diffusion method.

• Broth dilution tests: Determine MIC and minimal bactericidal concentration (MBC) using serial dilutions.

• Antibiograms: Reports of clinical susceptibility patterns.

Antimicrobial Drug Resistance

Mechanisms of Resistance

• Enzymatic destruction or inactivation: e.g., β-lactamases break down β-lactam antibiotics.

• Prevention of penetration: Modified porins in gram-negative bacteria block drug entry.

• Alteration of target site: e.g., MRSA modifies penicillin-binding proteins.

• Rapid efflux: Membrane pumps expel antibiotics from the cell.

Spread and Impact of Resistance

• Resistance genes often spread via plasmids or transposons (horizontal gene transfer).

• Superbugs: Bacteria resistant to multiple antibiotics (e.g., Acinetobacter baumannii, Pseudomonas aeruginosa).

• Persister cells: Survive antibiotic exposure due to genetic traits.

Prevention of Resistance

• Finish prescribed antibiotic courses.

• Avoid unnecessary prescriptions and use narrow-spectrum drugs when possible.

• Do not use leftover or someone else's antibiotics.

Drug Safety and Combinations

• Therapeutic index: Ratio of risk to benefit; higher index indicates safer drugs.

• Synergism: Combined effect of drugs is greater than individual effects.

• Antagonism: Combined effect is less than individual effects.

Future Directions in Antimicrobial Therapy

• Targeting virulence factors and dormant cells.

• Developing drugs for gram-negative bacteria and nonculturable pathogens.

• Exploring antimicrobial peptides (bacteriocins) and phage therapy.

• Investigating the microbiome for new antibiotics.