CHEM2011 Lecture 2 Antibiotics
Study
beta-lactams
4M-cyclic amide substituted next to nitrogen (beta position)
Penicillin G properties
-active against gram +ve and some gram -ve
-non-toxic even at high doses
-must be injected otherwise hydrolysed in acidic stomach
-ineffective against bacteria producing beta-lactamases
-might be allergic to it
cause of penicillin allergy
mode of action - it rapidly releases antigenic bacterial membrane proteins
essential elements in SAR
-alpha-subtd amide
-beta-lactam ring
-cis stereochemistry at alpha and beta
-fused 5/6MR at alpha and ring amide
-free acid on fused ring
penicillin acid instability due to
poor overlap of nitrogen lone pair with carbonyl - carbonyl more electrophilic, easy to
reduce/hydrolyse
degradation of penicillin G major route
intramolecular cyclisation, gives penillic acid
degradation of penicillin G minor route
direct water attack, gives penicilloic acid
first orally active penicillin and modification from G?
penicillin V, -CH2OPh group on alpha amide
mechanism of acid hydrolysis resistance
PhO group electronegativity reduces adjacent carbonyl nucleophilicity therefore more
stable to acidic conditions
bacteria electrolyte dependency
require high [K+] inside membrane, moderated by Na+/K+ pump to avoid osmotic
pressure inside membrane leading to cell rupture :(
bacterial cell wall structure (gram +ve)
-outer cell wall with peptidoglycan and teichoic acid
-cytoplasmic membrane containing lipoteichoic acid and transpeptidases
-cytoplasm on inside
bacterial cell wall structure (gram -ve)
-outer membrane with porins, lipopolysaccharides
-periplasmic space with lipoproteins and peptidoglycan layer
-cytoplasmic membrane with transpeptidases
-cytoplasm on inside
beta-lactamases on gram +ve?
outside of cell wall
beta-lactamases on gram -ve?
in periplasmic space
Study
beta-lactams
4M-cyclic amide substituted next to nitrogen (beta position)
Penicillin G properties
-active against gram +ve and some gram -ve
-non-toxic even at high doses
-must be injected otherwise hydrolysed in acidic stomach
-ineffective against bacteria producing beta-lactamases
-might be allergic to it
cause of penicillin allergy
mode of action - it rapidly releases antigenic bacterial membrane proteins
essential elements in SAR
-alpha-subtd amide
-beta-lactam ring
-cis stereochemistry at alpha and beta
-fused 5/6MR at alpha and ring amide
-free acid on fused ring
penicillin acid instability due to
poor overlap of nitrogen lone pair with carbonyl - carbonyl more electrophilic, easy to
reduce/hydrolyse
degradation of penicillin G major route
intramolecular cyclisation, gives penillic acid
degradation of penicillin G minor route
direct water attack, gives penicilloic acid
first orally active penicillin and modification from G?
penicillin V, -CH2OPh group on alpha amide
mechanism of acid hydrolysis resistance
PhO group electronegativity reduces adjacent carbonyl nucleophilicity therefore more
stable to acidic conditions
bacteria electrolyte dependency
require high [K+] inside membrane, moderated by Na+/K+ pump to avoid osmotic
pressure inside membrane leading to cell rupture :(
bacterial cell wall structure (gram +ve)
-outer cell wall with peptidoglycan and teichoic acid
-cytoplasmic membrane containing lipoteichoic acid and transpeptidases
-cytoplasm on inside
bacterial cell wall structure (gram -ve)
-outer membrane with porins, lipopolysaccharides
-periplasmic space with lipoproteins and peptidoglycan layer
-cytoplasmic membrane with transpeptidases
-cytoplasm on inside
beta-lactamases on gram +ve?
outside of cell wall
beta-lactamases on gram -ve?
in periplasmic space
