Antimicrobial Drugs: Chemotherapy & Antibiotics

Antimicrobial Drugs - An Overview

• Chemotherapy with antimicrobial drugs is utilized when the body's defenses cannot overcome a disease
• These drugs eliminate or hinder the growth of microorganisms, operating within the host without harm, a concept termed selective toxicity
• Antibiotics were a significant advancement, effectively treating lethal infectious diseases previously untreatable
• Current advances face the challenge of antibiotic resistance
• Infections from staphylococcal pathogens resist most antibiotics
• Pathogens causing tuberculosis are now resistant to many antibiotics once effective
• It has become increasingly difficult to treat diseases caused by resistant pathogens, and fewer treatment options are available

History and Development of Chemotherapy

• Chemotherapy began with Paul Ehrlich who sought a selective "magic bullet" to target pathogens, coining chemotherapy and selective toxicity
• Alexander Fleming discovered penicillin in 1928 from a Penicillium notatum-contaminated plate, naming its active compound penicillin
• Antibiosis is inhibitory reactions observed between microbial colonies on solid media leading to the term, antibiotic
• Sulfanilamide drugs, discovered from surveys by German scientists starting in 1927, were found to treat streptococcal infections in mice (Prontosil Red)

Antibiotic Use Today and Discovery

• More than 50% of antibiotics are derived from the bacterium Streptomyces which lives in soil
• Some antibiotics, such as the ones produced by endospore-forming bacteria, are primarily for commercial use rather than treatment of disease
• Finding new antibiotics requires greater urgency due to rising levels of antibiotic resistance

Spectrum of Antimicrobial Activity

• Finding drugs effective against prokaryotic cells is easier because they differ substantially in many ways from the eukaryotic cells of humans
• Eukaryotic pathogens resemble human cells more closely, and drugs targeting them often harm the host
• Viral infections are hard to treat because the virus is within the host's cells and redirects them to produce more viruses
• Some drugs have a narrow spectrum and affect a limited range of microbes, (Penicillin G)
• Broad-spectrum antibiotics affect a wide range of bacteria, but can destroy normal microbiota
• Destruction of normal microbiota lets survivors thrive and become opportunistic pathogens, causing superinfections (Candida albicans)

Mechanisms of Action

• Antimicrobial drugs can kill (bactericidal) or prevent microbial growth (bacteriastatic)
• Bacteriostasis requires the host's own defenses for microbial destruction

Inhibiting Cell Wall Synthesis

• The synthesis of peptidoglycan is inhibited by Penicillin and other antibiotics leading to cell lysis especially since bacteria have cell walls and human cells do no
• Penicillin primarily impacts actively growing cells

Inhibiting Protein Synthesis

• Notable differences between the 70S and 80S ribosome enables selective antibacterial toxicity

Injuries to Plasma Membrane

• Polypeptide antibiotics change membrane permeability and cause metabolite loss
• Ionophores, produced by soil bacteria and fungi, are not consumed by humans, but rather by cattle, as they improve digestion and promote the uncontrolled movement of cations across the plasma membrane
• Some antifungals target sterols in fungal plasma membranes

Nucleic Acid Synthesis

• Some antibiotics interfere with DNA replication and transcription in bacteria by blocking bacterial topoisomerase or RNA polymerase

Synthesis of Metabolites

• Enzymatic activities are competitively inhibited by antimetabolites
• Sulfanilamide competitively inhibit folic acid production

Common Antibacterial Drugs

• To act as a "magic bullet," antibiotics usually target microbial functions or structures that differ from mammalian ones
• The mammalian cell lacks a cell wall making its an attractive antibiotic target

Penicillin

• Refers to over 50 chemically related antibiotics that have a common core structure including a B-lactam ring
• Types vary by chemical side chains attached to the nuclei
• Prevent cross-linking of peptidoglycans in gram-positive bacteria by interfering with cell wall synthesis
• Can be naturally or semi-synthetically produced

Natural Penicillins

• Natural penicillins extracted from Penicillium fungi are prototype compound