Lecture 8 Antibacterial drugs targeting the cell envelope

Question 1

Name examples of classes of drugs that inhibit peptidoglycan synthesis

Answer 1

B-lactams
Vancomycin
Bacitracin
Cycloserine
Fosfomycin

Question 2

Name examples of classes of drugs that affect bacterial membranes

Answer 2

Polymyxin/colistin

Daptomycin

Question 3

What are the 2 glycan strands that make up the peptidoglycan wall?

Answer 3

N-acetylmuramic acid (NAM)

N-acetylglucosamine (NAG)

Question 4

Describe the structure of the peptidoglycan wall

Answer 4

Chains of alternate NAM and NAG joined together = transglycosylation
Chains are then cross linked via stem peptides on NAM via the transpeptidase domain of PBP enzyme = transpeptidation

Question 5

What is the function of the peptidoglycan wall?

Answer 5

To protect against osmotic pressure and the cell bursting

Question 6

Name the enzyme that catalyses transglycosylation and transpeptidation

Answer 6

penicillin binding proteins (PBP)

Question 7

Explain the mechanism of action of B-lactams

Answer 7

B lactams enter through porins
Binds to PBP = blocks transpeptidation i.e. cross linking does not occur which leads to cell lysis
Hydrolysis of peptidoglycan wall happens normally in order to be remodelled, especially at a division site - this procress still occurs during the presence of B-lactams = protrusion of cytoplasmic membrane (spheroplast) and osmosis/cell death

Question 8

What are the clinical uses of B-lactams?

Answer 8

Widespread use on almost all types of bacteria
Syphilis
Strep pyogenes

Question 9

What side effects can occur in patients using B-lactams?

Answer 9

Hypersensitivity reaction - issomerisation of penicillin which attaches to host proteins
Common with benzylpenicillin
1-5% of patients
Variety of skin eruptions
Rare: anaphylactic shock = circulatory collapse, bronchospasms, coma, death

Question 10

How are B-lactamases a threat to the action of B-lactams? How has this been overcome?

Answer 10

Resistance adaptation - evolutionary adapted to transpeptidase
Inhibits the action of B lactams by opening the B-lactam ring
Addition of B-lactamse inhibitors given with B-lactams

Question 11

What are the 4 types of B-lactams?

Answer 11

Penicillins
Cephlosporins
Monobactams
Carbapenems

Question 12

In what form is cephalosporins given and for what use?

Answer 12

IV/IM
Broad spectrum
Most clinically used B-lactam
First generation mostly targeted gram +ve but newer generations also have gram -ve activity

Question 13

Describe the clinical uses of carbapenems

Answer 13

Very broad spectrum

Gram -ve multi-resistance bacteria mainly - last line used

Question 14

Describe the mode of action of vancomycin

Answer 14

Works via steric hinderence of D-ala-D-ala
Attaches to D-ala-D-ala to inhibit transpeptidase binding and causing crosslinking
Therefore cell wall formation does not occr

Question 15

Describe the clinical uses of vancomycin

Answer 15

Gram +ve bacteria only - due to large size of molecule therefore cannot get through the cell wall
Normally used when B-lactams cannot be
IV: serious infections by S.aureus e.g. MRSA and other gram +ve pathogens e.g. enterococci
Given orally for C.Diff infections

Question 16

What are the side effects associated with vancomycin?

Answer 16

Rapid administration = release of histamine, ‘red man’ syndrome
Nephro and ototoxic sometimes
Reversible neurtropenia and thrombocytopenia

Question 17

How does bactiracin work?

Answer 17

binds to membrane carrier molecule that transports NAM-NAG + peptide strand from cytosol to outer wall called undecaprenyl diphosphate = prevents dephosphorylation

Question 18

How does fosfomycin work?

Answer 18

covalently inhibits MurA by binding to active site cysteine residue

Question 19

How does D-cycloserine work?

Answer 19

competitive inhibitor of Alanine rasinase & Ddl = peptide strand unable to be formed

Question 20

Describe the clinical use of polymycin B and colistin (Polymycin E)

Answer 20

Toxic effects meant reduced use in the past
Now needing to be used more due to resistance
Multi resistant gram -ve pathogens
Pseudomonas infections including inhalation therapy for CF
Selective decontamination of the gut
Burns infections

Question 21

Describe the mode of action of polymycin B and colistin (Polymycin E)

Answer 21

Initially interacts with outer lipopolysaccharide leaflet of gram -ve membrane
Penetrates through the outer membrane and into inner cytoplasmic membrane
Flip flops between membranes or aggregates in membrane to destabilise membrane
= depolarisation of membrane and leaking of intracellular content

Question 22

What are side effects that can occur from polymycins?

Answer 22

Neurotoxicity and nephrotoxicity when given parenterally (20-25% of patients)

Question 23

Describe the mode of action of daptomycin

Answer 23

Inserts into the membrane via a lipophilic tail and Ca
Aggregation of daptomycin
Membrane depolarisation, leakage of contents and cell death

Question 24

Describe the clinical use of daptomycin

Answer 24

gram +ve
Treatment for complicated skin/soft tissue infections e.g. caused by S. aureus and MRSA
IV

Question 25

What are side effects that can occur from daptomycin

Answer 25

dose needs adjusting for renal impairment

Muscle toxicity in <5% of patients