Antimicrobial Drugs: Mechanisms, Classes, and Resistance

Chapter 20: Antimicrobial Drugs

Introduction to Chemotherapy and Antimicrobial Drugs

Chemotherapy refers to the use of chemicals to treat diseases, particularly infections caused by microorganisms. Antimicrobial drugs are substances that interfere with the growth of microbes, while antibiotics are natural products produced by microbes that inhibit or kill other microbes. The concept of selective toxicity is central to chemotherapy, aiming to destroy pathogens without harming the host.

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

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

• Antimicrobial drugs: Synthetic or natural substances that inhibit microbial growth.

Historical Contributions

• Paul Ehrlich: Coined the term 'chemotherapy' and developed the first synthetic antimicrobial, Salvarsan, for syphilis.

• Alexander Fleming: Discovered penicillin in 1928, the first true antibiotic, produced by the mold Penicillium.

• Prontosil: The first commercially available antibacterial drug (a sulfa drug) introduced in 1932.

Spectrum of Antimicrobial Activity

Definitions and Concepts

Antimicrobial drugs vary in their spectrum of activity, which refers to the range of microbes they affect.

• Narrow-spectrum antibiotics: Effective against a limited group of bacteria (e.g., only Gram-positive bacteria).

• Broad-spectrum antibiotics: Effective against a wide variety of Gram-positive and Gram-negative bacteria.

• Superinfection: The overgrowth of resistant microbes or normal microbiota when broad-spectrum antibiotics eliminate competing organisms.

Mechanisms of Action of Antimicrobial Drugs

Major Modes of Action

Antimicrobial drugs target essential functions in microbes, exploiting differences between microbial and host cells.

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

• Inhibition of protein synthesis: e.g., chloramphenicol, erythromycin, tetracyclines, streptomycin (targeting 70S ribosomes unique to prokaryotes).

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

• Injury to plasma membrane: e.g., polymyxin B, daptomycin.

• Inhibition of essential metabolite synthesis: e.g., sulfonamides, trimethoprim (antimetabolites).

Bactericidal vs. Bacteriostatic

• Bactericidal: Drugs that kill microbes directly.

• Bacteriostatic: Drugs that inhibit microbial growth, allowing the immune system to eliminate the pathogen.

Inhibition of Cell Wall Synthesis

• Penicillins prevent the cross-linking of peptidoglycan, weakening the cell wall and causing lysis, especially in Gram-positive bacteria.

Inhibition of Protein Synthesis

• Antibiotics target bacterial 70S ribosomes, which differ from eukaryotic 80S ribosomes, minimizing host toxicity.

• Examples: Chloramphenicol (binds 50S subunit), tetracyclines (block tRNA attachment), streptomycin (alters 30S subunit).

Injury to Plasma Membrane

• Polypeptide antibiotics (e.g., polymyxin B) disrupt membrane integrity, causing leakage of cell contents.

• Antifungal drugs often target ergosterol in fungal membranes.

Inhibition of Nucleic Acid Synthesis

• Drugs like quinolones and rifampin interfere with DNA replication or transcription.

Inhibition of Essential Metabolite Synthesis

• Sulfonamides and trimethoprim inhibit folic acid synthesis, which is essential for nucleic acid and protein synthesis in bacteria.

Major Classes of Antibacterial Drugs

Inhibitors of Cell Wall Synthesis

• Penicillins: Natural (Penicillin G, V), semisynthetic (oxacillin, ampicillin), and penicillinase-resistant types.

• Cephalosporins: Grouped by generations, with increasing activity against Gram-negative bacteria and resistance to β-lactamases.

• Carbapenems and Monobactams: Broad-spectrum β-lactam antibiotics (e.g., imipenem, aztreonam).

• Polypeptide antibiotics: Bacitracin (topical), vancomycin (last line for MRSA), teixobactin (new class).

• Antimycobacterial antibiotics: Isoniazid and ethambutol target mycolic acid synthesis in Mycobacterium spp.

Inhibitors of Protein Synthesis

• Chloramphenicol: Broad spectrum, binds 50S subunit, can suppress bone marrow.

• Aminoglycosides: (e.g., streptomycin, neomycin, gentamicin) change 30S subunit shape, can cause auditory damage.

• Tetracyclines: Broad spectrum, interfere with tRNA attachment, effective against intracellular pathogens.

• Macrolides: (e.g., erythromycin) narrow spectrum, mainly Gram-positive bacteria.

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

Injury to Plasma Membrane

• Lipopeptides: Daptomycin (skin infections), polymyxin B (topical, Gram-negative bacteria), polymyxin E (colistin).

Nucleic Acid Synthesis Inhibitors

• Rifamycins: Inhibit mRNA synthesis, used for tuberculosis.

• Quinolones/Fluoroquinolones: Inhibit DNA gyrase (e.g., ciprofloxacin).

Competitive Inhibitors of Essential Metabolites

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

• Trimethoprim: Often combined with sulfonamides for synergistic effect.

Antifungal, Antiviral, Antiprotozoan, and Antihelminthic Drugs

Antifungal Drugs

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

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

• Agents inhibiting nucleic acids: Flucytosine.

• Other: Griseofulvin (inhibits microtubules), tolnaftate (athlete’s foot), pentamidine (Pneumocystis pneumonia).

Antiviral Drugs

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

• Uncoating, genome integration, and nucleic acid synthesis inhibitors: e.g., acyclovir, zidovudine.

• Assembly and exit inhibitors: Protease inhibitors, neuraminidase inhibitors (e.g., oseltamivir).

• Interferons: Proteins produced by infected cells to inhibit viral spread.

Antiprotozoan and Antihelminthic Drugs

• Antiprotozoan: Chloroquine, artemisinin (malaria), metronidazole (amebic infections), miltefosine (leishmaniasis).

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

Testing Microbial Susceptibility

Diffusion Methods

• Disk-diffusion (Kirby-Bauer) test: Paper disks with antibiotics are placed on agar; zones of inhibition indicate sensitivity.

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

Broth Dilution Tests

• Determine MIC and minimal bactericidal concentration (MBC) by observing growth in wells with different drug concentrations.

Resistance to Antimicrobial Drugs

Mechanisms of Resistance

• Enzymatic destruction or inactivation: e.g., β-lactamases inactivate penicillins.

• Prevention of penetration: Altered cell wall or membrane restricts drug entry.

• Alteration of target site: Mutation changes drug binding site (e.g., ribosome modification).

• Efflux pumps: Bacteria expel antibiotics using membrane proteins.

Spread of Resistance

• Resistance genes can be transferred horizontally (plasmids, transposons, conjugation, transduction) or vertically (cell division).

• Superbugs are bacteria resistant to multiple antibiotics.

Antibiotic Misuse

• Misuse (e.g., incomplete regimens, use for viral infections, animal feed) accelerates resistance development.

Antibiotic Safety and Drug Combinations

• Therapeutic index: Ratio of toxic dose to therapeutic dose; higher index indicates greater safety.

• Synergism: Combined effect of two drugs is greater than either alone (e.g., TMP-SMZ).

• Antagonism: Combined effect is less than either alone (e.g., tetracycline may interfere with penicillin).

Future Directions in Chemotherapy

• Research focuses on targeting virulence factors, sequestering iron, developing antimicrobial peptides (bacteriocins), and phage therapy.