Chapter 20 – Antimicrobial Drugs (Microbiology: An Introduction)
History of Chemotherapy
Selective toxicity: ability to destroy pathogens without harming the host.
Chemotherapy: treatment of disease with chemicals.
Antibiotic: substance produced by a microbe that, in small amounts, inhibits another microbe.
Antimicrobial drug: synthetic substance that interferes with microbial growth.
Representative Sources of Antibiotics
Gram-positive rods
Bacillus subtilis: Bacitracin
Paenibacillus polymyxa: Polymyxin
Actinomycetes
Streptomyces nodosus: Amphotericin B (polyenes)
Streptomyces venezuelae: Chloramphenicol
Streptomyces aureofaciens: Chlortetracycline & tetracycline
Saccharopolyspora erythraea: Erythromycin
Streptomyces fradiae: Neomycin
Streptomyces griseus: Streptomycin
Micromonospora purpurea: Gentamicin
Fungi
Cephalosporium spp.: Cephalothin
Penicillium griseofulvum: Griseofulvin
Penicillium chrysogenum: Penicillin
Spectrum of Antimicrobial Activity
Narrow spectrum: drug active against a limited range of microbes.
Broad spectrum: drug active against a wide range of Gram-positive or Gram-negative bacteria.
Superinfection: over-growth of normal microbiota that are antibiotic-resistant, often after broad-spectrum therapy.
Bactericidal vs. Bacteriostatic
Bactericidal: kill microbes directly.
Bacteriostatic: stop microbial growth; host defenses then remove pathogens.
Major Modes of Action of Antibacterial Drugs
Inhibition of cell-wall synthesis: penicillins, cephalosporins, bacitracin, vancomycin.
Inhibition of protein synthesis (targets 70S ribosomes): chloramphenicol, erythromycin, tetracyclines, streptomycin, nitrofurantoin.
Inhibition of nucleic-acid replication/transcription: quinolones, fluoroquinolones, rifampin.
Injury to plasma membrane: polymyxins, lipopeptides.
Inhibition of essential metabolite synthesis: sulfanilamide, trimethoprim (synergistic combo \text{TMP} + \text{SMZ}).
Inhibitors of Cell-Wall Synthesis
Penicillins
Prevent cross-bridge formation in peptidoglycan.
Natural forms: Penicillin G (parenteral), Penicillin V (oral); narrow spectrum; destroyed by \beta-lactamase.
Antimycobacterial antibiotics (narrow-spectrum)
Isoniazid (INH): inhibits mycolic-acid synthesis.
Ethambutol: blocks incorporation of mycolic acid into wall.
Inhibitors of Protein Synthesis
Act selectively on bacterial 70S ribosome, sparing eukaryotic 80S (selective toxicity).
Chloramphenicol: binds 50S; inhibits peptide-bond formation.
Streptomycin: alters 30S shape; misreading of mRNA.
Tetracyclines: block tRNA attachment to mRNA-ribosome complex.
Nitrofurantoin: chemically synthesized; reduced inside bacteria to intermediates that attack ribosomal proteins; urinary-tract use.
Injury to Plasma Membrane
Polypeptide antibiotics increase permeability.
Lipopeptides
Daptomycin: inserts into Gram-positive membranes.
Polymyxin B: topical; Gram-negative coverage.
Polymyxin E (Colistin): last-resort systemic therapy vs. multidrug-resistant Gram-negatives.
Antifungals bind membrane sterols (ergosterol).
Nucleic-Acid Synthesis Inhibitors
Rifamycin (rifampin): blocks bacterial RNA polymerase → no mRNA; antitubercular; induces hepatic enzymes ↑ drug metabolism.
Quinolones / Fluoroquinolones: e.g., Nalidixic acid; inhibit DNA gyrase (topoisomerase II) → DNA cannot replicate.
Antimetabolites (Competitive Inhibitors)
Sulfonamides resemble PABA; bind dihydropteroate synthase → stop folic-acid production.
Trimethoprim blocks dihydrofolate reductase → \text{DHF} \not\rightarrow \text{THF}.
Synergism: \text{FIC}A + \text{FIC}B < 1 for TMP-SMZ; combo becomes bactericidal.
Antifungal Drugs
Agents affecting ergosterol synthesis
Polyenes (Amphotericin B, Nystatin): form pores after binding ergosterol.
Azoles
Imidazoles (clotrimazole, miconazole): topical cutaneous infections.
Triazoles (fluconazole, itraconazole): systemic mycoses.
Agents affecting cell wall
Echinocandins (caspofungin): inhibit \beta-glucan synthesis → osmotic lysis.
Antiviral Drugs
Entry/Fusion inhibitors: block viral attachment (e.g., Maraviroc) or fusion (enfuvirtide).
Uncoating inhibitors: rimantadine, amantadine → capsid can’t release genome.
Genome-integration inhibitors: integrase strand-transfer inhibitors (raltegravir).
Nucleoside / nucleotide analogs
Acyclovir mimics deoxyguanosine; viral thymidine kinase phosphorylates → false nucleotide → DNA chain termination.
Non-nucleoside polymerase/RT inhibitors: efavirenz, nevirapine (bind reverse transcriptase allosterically).
Antiprotozoan Drugs
Quinine & Chloroquine: inhibit heme detoxification in Plasmodium; antimalarial.
Metronidazole, Tinidazole, Nitazoxanide: reduced in anaerobes → DNA/protein damage; treat Trichomonas, Giardia, Entamoeba; useful vs. some anaerobic bacteria.
Resistance to Antimicrobial Drugs
Persister cells: genetically poised to survive antibiotics.
Superbugs: MDR organisms; notable HAI threats: Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacteriaceae (e.g., KPC, NDM).
Mechanisms
Enzymatic destruction/inactivation (e.g., \beta-lactamase).
Decreased entry/porin mutation.
Altered target site (e.g., MRSA PBP2a).
Efflux pumps expel drug.
Combinational or novel variants of the above.
Study & Review Prompts
Contrast narrow vs. broad spectrum, bactericidal vs. bacteriostatic, and selective toxicity.
List the five major modes of antibacterial action + examples.
Explain how drugs target the 30S vs. 50S subunits and why human cytosolic ribosomes are not affected.
Outline mechanisms of microbial resistance and give clinical examples.
Summarize modes of action for antifungal, antiprotozoan, and antiviral drugs.
Name anti-mycobacterial drugs and their specific targets.
Describe how competitive inhibitors (sulfonamides, trimethoprim) exploit structural mimicry.
Suggested textbook questions: Review #1 (excluding ciprofloxacin, erythromycin, vancomycin), #4-5, #9; MC #2, 3, 5, 6.