Antibiotic chemistry

Question 1

difference between gram negative and positive bacterial cell wall?

Answer 1

gram positive has a thicker layer of peptidoglycan

Question 2

structure of peptidoglycan?

Answer 2

• alternating segments of NAG and NAM cross-linked by tetrapeptide

Question 3

how does activity of R group of Beta lactams change with EWG or bulky substituents?

Answer 3

EWG - N becomes less nucleophilic
bulky - steric hinderance to beta-lactamase

Question 4

what can the beta lactam ring be opened by?

Answer 4

OH, NH2, SH

Question 5

how does the carboxylic acid of beta lactams interact with enzyme?

Answer 5

negatively charged and forms salt bridge in enzyme pocket

Question 6

enzymes involved in bacterial cell wall synthesis?

Answer 6

penicillin binding proteins PBP or DD-transpeptidase

Question 7

mechanism of action of PBPs?

Answer 7

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

Question 8

what do beta lactams resemble?

Answer 8

tetrapeptide chains

Question 9

how do beta lactams work?

Answer 9

• 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

Question 10

how has resistance to beta-lactams come about?

Answer 10

bacteria evolved an enzyme (Beta-lactamases/penicillinases) that break the ring so antibiotics become ineffective

Question 11

2 solutions to combat resistance?

Answer 11

enzyme inhibitors - inactivate enzymes
newer antibiotics - larger side chains to not fit enzyme

Question 12

what makes penicillins unstable in acid?

Answer 12

amide side chain acts as an internal nucleophile which opens up the beta-lactam ring

Question 13

what makes penicillin V a weaker internal nucleophile?

Answer 13

add oxygen/ ether bond so O accepts electron density from C=O

Question 14

how do bactoprenol inhibitors such as bacitracin work?

Answer 14

block bactoprenol phosphate transporter so that new peptidoglycan cant be made

Question 15

role of bactoprenol phosphate transporter?

Answer 15

lets NAM and NAG cross membrane to synthesise new peptidoglycan

Question 16

what routes should bacitracin never be given by and why?

Answer 16

IV or IM as its highly nephrotoxic
- used topically for systemic infections

Question 17

how do beta-lactamase enzyme inhibitors work? (clavulanic acid, tazobactum)

Answer 17

permanently bind to enzyme to disable them so penicillins can work

Question 18

how do glycopeptide antibiotics work? (vancomycin)

Answer 18

inhibit cell wall synthesis by latching to tetrapeptide chain - prevents link to PBP enzyme

Question 19

how are glycopeptide antibiotics usually given?

Answer 19

not absorbed in GI tract so given IV typically