Antibiotic chemistry Flashcards
difference between gram negative and positive bacterial cell wall?
gram positive has a thicker layer of peptidoglycan
structure of peptidoglycan?
- alternating segments of NAG and NAM cross-linked by tetrapeptide
how does activity of R group of Beta lactams change with EWG or bulky substituents?
EWG - N becomes less nucleophilic
bulky - steric hinderance to beta-lactamase
what can the beta lactam ring be opened by?
OH, NH2, SH
how does the carboxylic acid of beta lactams interact with enzyme?
negatively charged and forms salt bridge in enzyme pocket
enzymes involved in bacterial cell wall synthesis?
penicillin binding proteins PBP or DD-transpeptidase
mechanism of action of PBPs?
1) cleavage of D-alanyl D-alanine bond of peptide unit precursor
2) acyl-enzyme intermediate formed
3) breakdown of intermediate to form new peptide bond
what do beta lactams resemble?
tetrapeptide chains
how do beta lactams work?
- PBP bind to antibiotic instead of tetrapeptide
- PBP becomes disabled, cross linking of peptidoglycan fails
- weakens cell wall
- bacteria attempt to divide and cell wall collapses, killing bacteria
how has resistance to beta-lactams come about?
bacteria evolved an enzyme (Beta-lactamases/penicillinases) that break the ring so antibiotics become ineffective
2 solutions to combat resistance?
enzyme inhibitors - inactivate enzymes
newer antibiotics - larger side chains to not fit enzyme
what makes penicillins unstable in acid?
amide side chain acts as an internal nucleophile which opens up the beta-lactam ring
what makes penicillin V a weaker internal nucleophile?
add oxygen/ ether bond so O accepts electron density from C=O
how do bactoprenol inhibitors such as bacitracin work?
block bactoprenol phosphate transporter so that new peptidoglycan cant be made
role of bactoprenol phosphate transporter?
lets NAM and NAG cross membrane to synthesise new peptidoglycan