Lecture 22 - Antibacterial agents Flashcards
What are the two major sources of antibacterial drugs?
- Soil microorganisms
- Chemical synthesis
What do bactericidal agents do generally?
Kills the bacteria
What do bacteriostatic agents do generally?
Inhibit reproduction of bacteria
What are the most common classes of antibacterial drug?
- Inhibitors of cell wall synthesis
- Inhibitors of transcription and translation
- Inhibitors of DNA synthesis and integrity
What are the functions of the bacterial cell wall?
- Maintain cell shape
- Give physical stregth to the cell
- Cope with osmotic and environmental challenges
- Secure cell during all stages of bacterial growth and propagation
- Provide important ligands for adherence
What makes gram-negative bacteria more recognizable as an antigen to the immune system?
The lipopolysaccharide in the outer membrane
What are bacterial cells walls made of?
Peptidoglycan
What is peptidoglycan?
Polysaccharide made up of:
- two cross-linked glucose derivatives (N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM))
- amino acids (L-alanine, D-glutamine, L-lysine, D-alanine
What are beta-lactam antibiotics?
A class of broad-spectrum antibiotics, consisting of all antibiotic agents that contain a beta-lactam ring in their molecular structures (ex. penicillins, cephalosporins, monobactams, and carbapenems)
Penicillin - Mechanism of action
- Bactericidal
- Inhibits transpeptidase and blocks peptidoglycan cross-linkage
- Disrupts cell-wall sythesis
What do beta-lactams do?
Binds to the transpeptidase active site and prevents crosslinking
Beta-Lactam antibiotics - Mechanism of action
B-lactams mimic D-ala-D-ala and bind to the active site of transpeptidase to inactivate it so it cannot catalyze the transfer of an amino acid or peptide group from one molecule to another
First generation penicillins
- Narrow spectrum
- Effective against gram-positive bacteria (ex streptococci)
- Not effective against gram-negative bacilli or organisms that produc penicillinase
- Ex. penicillin G, penicillin V
Second generation penicillins
- resistant to penicillinase
- effective against serious gram-negative infections
- ex. Ticarcillan, carbenicillin
Fourth generation penicillins
- Effective against gram-positive and negative bacteria
- Semi-synthetic
- Broad spectrum
- Ex. Mezlocilin
Mechanisms of bacterial resistance to beta-lactams - Penetration
Bacteria do not readily cross mammalian cell membranes, and bacteria that are within the cytoplasm of human cells are protected from exposure to high levels of antibiotics
Mechanisms of bacterial resistance to beta-lactams - Porins
Gram-negtive bacteria have an outer cell membrane that restricts drug access to the peptidoglycan cell wall to passage through porin channels
Mechanisms of bacterial resistance to beta-lactams - Pumps
Gram-negative bacteria can express P-glycoprotein-like ABC transporters in the outer membrane that function as efflux pumps to transport beta-lactam antibiotics out of the periplasmic space
Mechanisms of bacterial resistance to beta-lactams - Penicillinases
Most common mechanism for beta-lactam antibiotic resistance
(aka beta-lactamases)
Mechanisms of bacterial resistance to beta-lactams - PBP mutation
Bacteria can express a mutated PBP that still has enzymatic activity for cell wall synthesis, but does not bind to beta-lactam antibiotics (drug-insensitive)
Mechanisms of bacterial resistance to beta-lactams - Peptidoglycan absence
Some bacteria like mycobacteria lack a petidoglycan cell wall and can multiple in the prescence of b-lactam antibiotics
List of beta-lactamase inhibitors
- Penicillinase
- Augmentin
- Sulbactam
- Clavulanic acid
Why are some people allergic to penicillins?
Beta-lactams can modify amino groups on human proteins, creating an immunogenic b-lactam hapten
Vancomycin - Mechanism of action
Binds the C-terminal D-ala-D-ala residues and sterically twists the pentapeptide to prevent the cross-bridge formation between pentapeptide and pentaglycine
