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