Antimicrobial Drugs

Lecture Overview

  • Subject: Antimicrobials

  • Topics Covered:

    • History of Antimicrobial Drugs

    • Classifying Antimicrobial Drugs

    • Antibiotic drugs

    • Antifungal drugs

    • Antiviral drugs

    • Antiparasitic drugs

  • Source Material: Openstax Microbiology textbook Chapter 14

Classifying Antimicrobial Drugs

  • By Target Organism:

    • Antibacterial (Antibiotics)

    • Antiviral

    • Antifungal

    • Antiparasitic Drugs:

    • Antiprotozoal

    • Antihelminthic

  • By Origin:

    • Natural: Produced by microbes

    • Semisynthetic: Chemically modified natural products

    • Synthetic: Completely manufactured

  • By Spectrum of Activity:

    • Broad-spectrum: Active against many types (e.g., tetracyclines)

    • Narrow-spectrum: Active against specific group (e.g., penicillin G)

The Importance of Antimicrobial Drugs

  • Antimicrobial Drugs:

    • Therapeutic compounds that kill microbes or inhibit their growth

  • Prophylaxis:

    • Process that prevents infection or disease in a person at risk

  • Empiric Therapy:

    • Medical treatment begun on the basis of a clinical "educated guess" before the specific causative agent is known

The First Antimicrobial Drugs

Salvarsan

  • Year: 1909

  • Disease Treated: Syphilis

  • Causative Agent: Treponema pallidum

  • Previous Treatment: Mercury

  • Pioneers:

    • Sahachiro Hata: Screened arsenic compounds for anti-syphilitic properties, identifying compound 606

    • Paul Ehrlich: First synthesized Salvarsan, which proved effective against syphilis

Penicillin

  • Discoverer: Alexander Fleming (1928)

  • Significance: First naturally produced antimicrobial

  • Contributors to Production:

    • Howard Florey and Ernst Chain: Discovered the methods to scale up production and purify penicillin; demonstrated its efficacy in animal and human trials in the early 1940s

History of Antimicrobial Drugs

  • Paul Ehrlich (1910): Developed Salvarsan to treat syphilis; introduced the "magic bullet" concept

  • Alexander Fleming (1928): Discovered penicillin from the Penicillium mold

  • Chain and Florey (1940s): Purified and mass-produced penicillin during WWII

  • Selman Waksman: Discovered streptomycin, the first antibiotic effective against tuberculosis

  • Golden Age of Antibiotics: 1940s–1960s

Antibiotic Drug Classification

By Cellular Targets

  • Cell Wall:

    • β-lactams:

    • Penicillins

    • Cephalosporins

    • Monobactams

    • Carbapenems

    • Glycopeptides: Vancomycin, bacitracin

  • Membranes:

    • Polymyxins:

    • Polymyxin B

    • Colistin

    • Lipopeptide: Daptomycin

  • Cytoplasm:

  • Ribosomes:

    • 30S subunit:

    • Aminoglycosides (e.g., streptomycin)

    • Tetracyclines

    • 50S subunit:

    • Macrolides

    • Lincosamides

    • Chloramphenicol

    • Oxazolidinones

  • DNA Synthesis:

    • Fluoroquinolones (e.g., ciprofloxacin, levofloxacin, moxifloxacin)

  • RNA Synthesis:

    • Rifamycins (e.g., rifampin)

  • Metabolic Pathways:

    • Folic Acid Synthesis:

    • Sulfonamides

    • Sulfones

    • Trimethoprim

    • Mycolic Acid Synthesis:

    • Isoniazid

Major Mechanisms of Action

  • Antimicrobial drugs target key microbial processes:

    • Cell Wall Synthesis

    • Protein Synthesis

    • Nucleic Acid Synthesis

    • Plasma Membrane Integrity

    • Metabolic Pathways (Antimetabolites)

Antibiotic Drugs: Inhibitors of Cell Wall Synthesis

  • β-lactam Antibiotics:

    • Include penicillins, cephalosporins, and carbapenems

    • Structure: Contain a β-lactam ring

    • Target: Cell wall synthesis

    • Mechanism of Action:

    • Bind transpeptidase (penicillin-binding protein, PBP)

    • Block transpeptidation step in peptidoglycan cross-linking

    • Effect: Bactericidal; causes cell lysis

Importance of Peptidoglycan Cross-Linking

  • Description:

    • Sugar chains of peptidoglycan are cross-linked by proteins.

    • Penicillin blocks transpeptidase enzymes from building cross-links in the peptidoglycan cell wall, leading to a weak wall that cannot protect the cell from lysing (bursting).

Vancomycin

  • Target: Cell wall synthesis

  • Mechanism of Action:

    • Binds to the terminal amino acids of the pentapeptide (peptidoglycan monomer)

    • Inhibits assembly of peptidoglycan

  • Effect: Bactericidal; causes cell lysis

  • Spectrum: Effective against Gram-positive bacteria only

  • Clinical Use: Especially effective against Methicillin Resistant Staphylococcus aureus (MRSA)

Antibiotics: Inhibitors of Bacterial Protein Synthesis

  • Target: Bacterial protein synthesis

  • Note: Bacterial 70S ribosome is different from eukaryotic 80S

  • Types of Antibiotics:

    • Aminoglycosides:

    • Mode of Action: Bind 30S subunit, causing misreading of mRNA

    • Examples: Streptomycin, Gentamicin

    • Tetracyclines:

    • Mode of Action: Bind 30S subunit, blocking tRNA binding at A-site

    • Macrolides:

    • Mode of Action: Bind 50S subunit, blocking ribosome translocation and no peptide bond formation

    • Examples: Azithromycin, Erythromycin

Antibiotics: Inhibitors of Nucleic Acid Synthesis

  • Characteristics: Bactericidal

  • Types:

    • Quinolones/Fluoroquinolones (Ciprofloxacin):

    • Target: DNA synthesis

    • Mechanism of Action: Inhibit bacterial DNA gyrase, preventing DNA replication

    • Rifamycins (Rifampin):

    • Target: RNA synthesis

    • Mechanism of Action: Bind RNA polymerase, blocking transcription

    • Metronidazole:

    • Target: DNA

    • Mechanism of Action: Activated under anaerobic conditions, damages DNA

Antibiotics: Inhibitors of Metabolic Pathways

  • Sulfonamides (Sulfa Drugs) and Trimethoprim:

    • Mechanism of Action: Inhibit steps in folic acid synthesis

    • Note: Humans obtain folate from diet → selective toxicity

    • Synergistic Effect:

    • Combination (TMP-SMX or Bactrim) blocks sequential steps, leading to greater efficacy

  • Target: Folate (folic acid) synthesis

  • Broad-spectrum: Bacteriostatic

Antibiotics: Disruption of Plasma Membranes

  • Issue: Human and microbial membranes are similar, making selective toxicity challenging

  • Types of Antibiotics:

    • Polymyxins (B, E/Colistin):

    • Target: Cell membranes

    • Mechanism of Action: Interact with LPS in Gram-negative bacteria, disrupting membrane

    • Note: Toxic to kidneys, mainly used topically

    • Daptomycin:

    • Target: Cell membranes

    • Mechanism of Action: Inserts into Gram-positive membranes, depolarizing the cell

Antifungal Agents

  • Challenges:

    • Fungi are eukaryotic, leading to fewer selective targets

  • Common Targets:

    • Fungal cell walls

    • Fungal plasma membranes

    • Fungal nucleic acid synthesis

    • Chitin biosynthesis

    • Microtubules

    • Ergosterol synthesis, which is a common target of antifungal drugs

    • Like antibiotic resistance, antifungal resistance is on the rise

Ergosterol as a Target for Antifungals

  • Key Differences in Sterol Composition:

    • Predominant sterol in human cells is cholesterol

    • Predominant sterol in fungi is ergosterol, making ergosterol a good target for antifungal drug development.

Antiviral Drugs

  • Role: Treat infections but do not typically cure them

  • Mechanism: Target steps in the viral replication pathway

  • Effect: Usually limit infections rather than cure them

  • Note: Fewer options compared to antibiotics

Types of Antiviral Drugs

  • Entry Inhibitors:

    • Block viral attachment/fusion (e.g., maraviroc for HIV)

  • Nucleoside Analogs:

    • Mimic nucleotides → cause chain termination

    • Examples: Acyclovir (for HSV), AZT (for HIV)

  • Reverse Transcriptase Inhibitors:

    • Block RNA → DNA synthesis (HIV)

  • Protease Inhibitors:

    • Inhibit viral protein processing

  • Neuraminidase Inhibitors:

    • Prevent viral release (e.g., oseltamivir for influenza)

Antiparasitic Agents

  • Challenges in Development:

    • Both the pathogen and host are eukaryotes

    • Parasites have complex life cycles

    • A drug targeting one stage may be ineffective against other stages

  • Types of Antiparasitic Drugs:

    • Antimalarial Drugs:

    • Quinine, Chloroquine, Primaquine

    • Cinchona bark extract treats malaria

    • Effect: Increases vacuole pH; disrupts membrane stability

    • Antihelminthic Drugs:

    • Praziquantel (Biltricide): Alters membrane permeability in worms

    • Mebendazole: Inhibits microtubule function in helminths

    • Antiprotozoan Drugs:

    • Metronidazole (Flagyl): Treats intestinal/vaginal protozoa (and anaerobic bacteria)

Learning Objectives

  • After attending the lecture and completing assigned readings, the student will:

    • Compare and contrast natural, semisynthetic, and synthetic antimicrobial drugs

    • Describe historically important individuals and events leading to the development of antimicrobial drugs

    • Define: empiric therapy and prophylaxis

    • Contrast bacteriostatic versus bactericidal antibacterial activities

    • For each antibiotic drug class, identify: cellular target (mode of action) and whether they are bacteriostatic or bactericidal

    • Identify the 3 drug classes considered beta-lactam drugs

    • Compare/contrast the mechanism of action of antibacterial, antiviral, antifungal, and antiparasitic drugs