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