Antibacterial Antibiotics

Antibacterial Antibiotics

Historical Overview

• Molded curd of soybean used to treat boils and carbuncles in Chinese folk medicine
• 1877: Pasteur and Joubert discovered that anthrax bacilli were killed by certain bacteria
• 1909: Ehrlich's discovery of Arsphenamine
• 1929: Fleming's discovery of penicillin
• 1935: Domagk's discovery of sulfa drugs
• 1938: Florey and Chain introduced penicillin in therapy
• Waksman defined antibiotics as substances produced by microorganisms that inhibit growth or destroy other microorganisms

Ideal Antibiotic

• Selectively toxic (magic bullet)
• Chemically stable
• Slow rate of elimination for dosing schedule, but rapid and complete removal

Commercial Production

• Preparation of pure culture
• Fermentation
• Isolation
• Purification
• Assays
• Formulation

Review of Bacteria

Differences between Bacterial and Animal Cells

• Bacterial cells lack a defined nucleus
• Bacterial cells are simpler and lack organelles
• Bacterial cells have a cell membrane and cell wall
• Biochemistry of bacterial cells differs from animal cells
• Ribosomes: 70S in bacteria, 60S + 40S in animals

Mechanisms of Antibacterial Action

• MOA of antibiotics varies
• Understanding MOA is basis for future development of antibacterial antibiotics
• Antibiotics can be either bacteriostatic (inhibit growth) or bactericidal (kill)
• Five mechanisms of antibacterial action:
  1. Inhibition of cell wall synthesis
  2. Interactions with DNA or RNA
  3. Inhibition of nucleic acid synthesis
  4. Disruption of protein synthesis
  5. Inhibition of cell metabolism

Specific Antibacterial Agents

• Chemical classification:
  • Penicillins, cephalosporins (B-lactam ring)
  • Tetracyclines (4-annulated rings)
  • Aminoglycosides (amino sugars)
  • Macrolides (large lactone ring)
  • Bacitracins, polymyxins (polypeptides)
  • Newer agents

Inhibitors of Cell Wall Synthesis

• B-lactam antibiotics
• Penicillins, cephalosporins, monobactams, and carbapenems
• Beta-lactam ring is responsible for antibacterial activity

The Bacterial Cell Wall

• Absent from mammalian cells
• Potential for selective chemotherapy
• Functions:
  1. Semipermeable barrier
  2. Barrier from osmotic pressure changes
  3. Prevent digestion by host enzymes

Beta-Lactam Antibiotics

• Possess B-lactam ring
• Penicillin G and Penicillin V are agents of choice
• Potent, rapid bactericidal action
• Low toxicity
• Inhibit synthesis of peptidoglycan

Penicillin-Binding Proteins (PBPs)

• PBP 1a, 1b, 2, 3, 4, 5, and 6
• Inhibition of PBPs leads to cell lysis or filamentous forms
• Different PBPs have different functions

The Penicillins

• Commercial production from Penicillium Chrysogenum
• Core nucleus: 6-aminopenicillanic acid (6-APA)
• Fermentation-derived: Pen G, Pen V, and 6-APA
• Sodium and potassium salts are crystalline, hydroscopic, and water soluble

Structure of Penicillin

• Beta-lactam ring
• Amino group
• Side chain (R-group)
• 6-APA is the core nucleus of penicillins

Nomenclature

• CAS: 6-acylamino-2,2-dimethyl-3-carboxylic acid
• USP: 4-thia-1-azabicycloheptone
• Simplified forms: "penam", "penicillanic acid", and "penicillin" + R-chain

Stereochemistry

• Three chiral centers: C2, C5, and C6

Biosynthesis of Penicillins

• Derived from two amino acids: L-cysteine and L-valine
• 6-APA is the core nucleus

Chemical Instabilities

• Most penicillins are acids
• Sodium and potassium salts are highly water-soluble
• Benzathine and procaine are poorly water-soluble (depot forms)
• Hygroscopic

Chemical Degradation

• Hydrolysis is the main cause of deterioration
• B-lactam amide bond is the most unstable bond

This quiz covers the introduction and historical overview of antibacterial antibiotics, including their mechanisms of action and specific types. It also touches on the concept of antibiosis and its discovery.