Week 11 Introduction to Antibiotics - Comprehensive Notes

Chemotherapy Defined

• In pharmacology, chemotherapy refers to drugs targeting microorganisms (bacteria, viruses, fungi, and other parasites) and cancer.
• These drugs are sometimes called cytotoxic drugs.
• In the general public and medical community, "chemotherapy" is commonly associated with cancer treatment.

Properties of Chemotherapy Drugs

• Chemotherapy drugs should target selective differences between infectious microorganisms or cancer cells and normal host cells.
• Ideally, these drugs should cause no damage to the structure or function of host cells and organs.
• The goal is selective toxicity, which involves inhibiting biochemical pathways or targets crucial for the survival and/or replication of the pathogen or cancer cell.

Mechanisms of Selective Targeting

• Unique Targets:
  • Drugs target a genetic or biochemical pathway unique to the pathogen or cancer cell.
  • Example: Penicillin antibiotics target the synthesis of the bacterial peptidoglycan cell wall.
  • Drugs for unique targets generally have a large therapeutic window.
• Selective Targets:
  • Drugs target a protein isoform unique to the pathogen or cancer cell.
  • Example: Inhibitors of the enzyme dihydrofolate reductase (crucial for nucleotide synthesis) can target specific isoforms in bacteria.
  • Drugs for selective targets generally have a smaller therapeutic window than unique targets.
• Common Targets:
  • Drugs target metabolic requirements specific to the pathogen or cancer cell.
  • Even if the pathogen/cancer cell shares common biochemical & physiological pathways with the host, targeting it could be effective if the pathogen requires the metabolic activity for survival, or is affected by its inhibition to a greater degree than the host.
  • Example: Drugs targeting DNA synthesis, mitosis, and cell cycle progression (bacteria and cancer cells divide more often than most host cells).
  • Drugs for common targets have a narrow therapeutic window.

Classification of Antibiotic Drugs

• The term "antibiosis," coined by Alexander Fleming, means "against life," referring to killing bacteria with antibiotics.
• Antibiotics can be classified by:
  • Class and spectrum of microorganisms killed.
  • Biochemical pathway interfered with.
  • Chemical structure of the drug moiety that binds to a specific microbial protein/receptor.

Antibiotics - Bacteriostatic vs. Bactericidal

• Bacteriostatic:
  • Targets metabolic pathways essential for growth but not survival.
  • Relies on the host immune system to kill bacteria.
• Bactericidal:
  • Antibiotics that kill bacteria directly.

Classes of Bacteria

• Examples include Staphylococci, Streptococci, Pneumococci, Neisseria meningitidis (meningococcal), Escherichia coli, Salmonella, Mycobacterium tuberculosis, Mycobacterium leprae.

Sites of Action of Antibiotics

• Antibiotics act on various sites such as:
  • Cell wall synthesis
  • Folic acid metabolism
  • DNA synthesis
  • RNA polymerase
  • Protein synthesis

Penicillins - β-Lactam Antibiotic

• Still one of the most important classes of antibiotics.
• Prototypic β-lactam antibiotic.
• Bactericidal.
• Resistance was detected very early.
• Examples include penicillin, amoxycillin, ampicillin.

Mechanism of Action of β-Lactams

• β-lactam antibiotics (e.g., penicillin) interfere with the synthesis of the bacterial cell wall, leading to bacterial death.
• They weaken the cell wall by inhibiting transpeptidases that cross-link peptide chains attached to the backbone of peptidoglycan.
• This weakening leads to bacterial cell lysis & death.
• β-lactams = bactericidal.
• NAM= N-Acetyl-muramic acid

Spectrum of Action

• The spectrum of action refers to the number of microbial species affected by an antimicrobial agent.
• Narrow Spectrum:
  • Effective against few species.
  • Example: Penicillin G is effective against Gram-positive bacteria and a few other microbes.
• Broad Spectrum:
  • Effective against many species.
  • Example: Tetracyclines are effective against Gram-positive and Gram-negative bacteria.
• This is not to be confused with a narrow or broad/large therapeutic window.

Antibiotic Resistance

• Microbes can become resistant to antibiotics.
• Two major driving forces:
  • Evolution of microbes (rapidly divide).
  • Clinical/environmental practices.
• Subjecting species to pressure (chemical/environmental) threatens extinction, leading to the evolution of mechanisms to survive under stress.
• Evolution of antibiotic resistance is aided by:
  • Poor therapeutic practices (e.g., prescribing antibiotics for viral infections).
  • Indiscriminate use in agriculture/animal husbandry.

How Antibiotic Resistance Develops

• Resistance may develop at any point in the process by which a drug reaches and binds to its target.
• Mechanisms include:
  • Reduced entry of antibiotic into the microbe.
  • Enhanced export of antibiotic by efflux pumps.
  • Release of microbial enzymes that destroy the antibiotic.
  • Changes to microbial proteins required for antibiotic action (pro-drugs).
  • Changes to the microbial target protein for antibiotics.
  • Development of alternative biochemical pathways to those inhibited by the antibiotic.

Mechanisms of Drug Resistance

• Drug unable to penetrate cell wall.
• Anaerobic conditions lead to a dormant/non-replicating state; drugs that block metabolic processes have no effect during this state (exceptions: rifamycin, fluoroquinolone).
• Alteration of enzyme prevents conversion of pro-drug to active form (pyrazinamide, isoniazid).
• Low pH renders drug inactive.
• Drug exported from cell before it reaches target.
• Mutations in DNA repair genes lead to multiple drug resistance (streptomycin, isoniazid, ethambutol).
• Alteration of target protein structure prevents drug recognition (rifamycin, ethambutol, streptomycin, fluoroquinolone, macrolide).

Antibiotic Resistance – β-Lactams

• Release of microbial enzymes that destroy the antibiotic.
• β-lactamases cleave the β-lactam ring of β-lactam class of antibiotics such as penicillin.
• Clavulanic acid is a β-lactamase inhibitor.

Review Questions

• Esma’s respiratory infection (pneumococcus) is treated with penicillin (antibiotic). What is the mechanism of action of penicillin?
  • Inhibition of bacterial cell wall synthesis.
• Developing new antibiotic drug: Rate the following cellular situations as MORE or LESS likely to cause harm to the host:
  • A. The bacteria synthesise DNA nucleotides using the same type of enzyme, but different isoform of the enzyme compared to the host cells - LESS
  • B. The bacteria is protected by a peptidoglycan cell wall - MORE
  • C. The bacteria synthesise proteins using the same enzymes but carries a single mutation not seen in the host cells - LESS
  • D. A unique protein triggers cell division in the bacteria - MORE
  • E. The bacteria uses the same enzymes to unfold DNA as the host cells - MORE
  • F. The bacteria synthesise proteins using the same type of enzyme, but different isoform of the enzyme compared to the host cells - LESS

Summary

• Chemotherapy and selective toxicity
  • Unique Targets
  • Selective Targets
  • Common Targets
• Sites of action of antibiotics
  • Cell wall synthesis inhibitors (penicillins - β-lactams)
  • Inhibitors of RNA and protein synthesis
  • Inhibitors of DNA synthesis or structure
• Narrow and broad spectrum of antibiotic action
• Antibiotic resistance

Recommended Readings

• Ritter, Flower, Henderson, Loke, MacEwan, Robinson & Fullerton. Pharmacology 10th Ed. Chapters 51 & 52
• Golan, Armstrong and Armstrong. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy 4th Ed. 2017 Chapters 33 & 35