L7 - Antibacterials : cell envelope

Question 1

What are antibac drugs that inhibit peptidoglycan synthesis?

Answer 1

B-lactams

vancomycin

Question 2

What are antibac drugs that affects bacterial membranes?

Answer 2

polymxin/colistin

daptomycin

Question 3

What is the structure of peptidoglycan?

Answer 3

N-acetylmuramic acid

N-acetylglucosamine

peptide bridge

Question 4

What happens during peptidoglycan biosynthesis?

Answer 4

3 stages

bulk reaction - stage 1 in bacterial cytoplasm

series of Mur enzymes reactions creating peptidoglycan precursors

Question 5

What is glycosytransfer?

Answer 5

polymerisation of the glycan strands

dissacharide portion of the molecule is incorporated into an existing glycan domain

Question 6

What is transpeptidation?

Answer 6

cross linking between glycans by STEM PEPTIDES

Question 7

What are stem peptides?

Answer 7

5 aa residues of both L and D form

Question 8

What are the final 2 residues of the stem peptides?

Answer 8

two D-Alanine residues

Question 9

what enzymes catalyse the glycosyltransfer and peptidase reaction?

Answer 9

same enzymes as the reaction is coupled

penicllin-binding proteins (PBPs)

bi-functional enzymes with separate domains

Question 10

What are the 2 antibiotic classes that interfere with final stages of cell wall biosynthesis?

Answer 10

B-lactams - penicillins, cephalosporins

glycopeptides - vancomycin, teicoplanin

Question 11

How do glycopeptides act?

Answer 11

bind to the D-alanine peptides at the end of stem peptide

Question 12

How do B-lactams act?

Answer 12

bind to the PBP enzyme

Question 13

What is the B-lactam mechanism of action?

Answer 13

broken B-lactam attaches covalently to the key catalytic residue

stops normal role of transpeptidation

cell wall loses mechanical rigidity

Question 14

What to peptidoglycan hydrolases do?

Answer 14

cleavage of PG for expansion of network

NOT inhibited by B-lactams

bacteria still breaks down its own material

Question 15

What are the clinical applications of B-lactams?

Answer 15

extensive use

SAFE

Question 16

What are side effects of B-lactams?

Answer 16

Hypersensitivity - benzylpenicillin

Anaphylactic shock after injection

Question 17

How does penicillin allergy occur?

Answer 17

small breakdown/isomerization of penicillin

benzylpenicillenic acid is produced - quite reactive with lysine residues

penicillin antigen is produced

Question 18

How do B-lactamases mediate resistance to B-lactams?

Answer 18

break open ring = inactive

Question 19

Ho are B-lactams protected by clavulanic acid?

Answer 19

inactivates the B-lactamase

irreverisble inhibited enzymes (double hit mechanism)

Question 20

Which B-lactamase inhibitor is the best?

Answer 20

AUGMENTIN = Clavanulate-Amoxicillin

Question 21

What are properties of penicillins?

Answer 21

modify R variable group

R group = how stable the drug is & stability against B-lactamase

Question 22

What are some therapeutic applications of penicillin G?

Answer 22

Pneumococcal pneumonia

Syphilis

Gonorrhea

Question 23

Which molecule is the only B-lactam to have 2 R-groups?

Answer 23

CEPHALOSPORINS

Question 24

what is the 4th generation cephalosporin?

Answer 24

cefepime

Question 25

What are 3 types of CARBAPENEMS?

Answer 25

Impienem Meropenem Ertapenem

Question 26

What is vancomycin?

Answer 26

natural product antibiotic

Question 27

How does vancomycin bind to D-ala-D-ala

Answer 27

H-bonding

Question 28

What is the mode of action of vancomycin?

Answer 28

PRIMARILY - transglycosylation SOME - transpeptidation - can sometimes catch the process

Question 29

Can vancomycin act against all bacteria?

Answer 29

NO - inactive against gram-neg

Question 30

What are the clinical applications of vancomycin?

Answer 30

IV - treat S.aureus, MRSA, gram-pos good for people hyper-sensititve B-lactam oral - C.diff

Question 31

What are the adverse side effects of vancomycin?

Answer 31

rapid taking = "red-man" syndrome nephrotoxic ototoxic reversible neutropenia & thrombocytopenia

Question 32

What are polymixins B/E?

Answer 32

cyclic lipopeptides use waned in 1980s but making a comeback

Question 33

What is the mode of action of polymyxins?

Answer 33

interacts with lipopolysaccharide penetrate OM penetrate IM flip-flop disrupt integrity

Question 34

Clinical applications of polymyxins?

Answer 34

Pseudomonas inhalation therapy - cystic fibrosis decontamination of gut burns ***MDR gram-neg infections*** VITAL LAST LINE DEFENCE

Question 35

What are side effects of polymyxins

Answer 35

no LPS on gram-pos = inactive neurotoxicity + nephrotoxicity when given parenterally (20-25%)

Question 36

What is Daptomycin

Answer 36

cyclic lipopeptide acyl chain makes the interaction

Question 37

How does daptomycin work?

Answer 37

interacts with membrane via acyl chain Helped by Ca2+ ions aggregation membrane depolarisation = leakage + death

Question 38

Why is daptomycin calcium-mediated?

Answer 38

otherwise repulsions between head group & membrane would occur

Question 39

What are the applications of daptomycin?

Answer 39

complicated skin/ soft tissue infections IV

Question 40

What are side effects of daptomycin?

Answer 40

NOT ACTIVE against gram-neg muscle toxicity