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

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 by peptide bridges 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 catalyzes 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 therefore cross-linking does not occur which leads to cell lysis
Hydrolysis of peptidoglycan wall happens normally, especially at a division site - this process still occurs during the presence of B-lactams which leads to protrusions of cytoplasmic membrane and osmotic lysis/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

Amongst the safest antibacterial drugs used
Hypersensitivity reaction
Common with benzylpenicillin
1-5% of patients
Variety of skin eruptions
Rare: anaphylactic shock = circulatory collapse, bronchospasms, coma, death

Question 10

How is 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-lactamase 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
The 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 - last line of defense

Question 14

Describe the mode of action of vancomycin

Answer 14

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

Question 15

Describe the clinical uses of vancomycin

Answer 15

Gram +ve bacteria only - due to the large size of the molecule, therefore, cannot get through the cell wall.
Normally used when B-lactams cannot be used.
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 neutropenia and thrombocytopenia

Question 18

What are side effects that can occur from polymyxins?

Answer 18

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

Question 19

Describe the clinical use of polymyxin B and colistin (Polymxcin E)

Answer 19

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 cystic fibrosis.
Selective decontamination of the gut.
Burns infections.

Question 20

Describe the clinical use of daptomycin

Answer 20

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

Question 21

What are side effects that can occur from daptomycin

Answer 21

the dose needs adjusting for renal impairment

Muscle toxicity in <5% of patients

Question 22

Describe the mode of action of polymyxin B and colistin (Polymyxin E)

Answer 22

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

Question 23

Describe the mode of action of daptomycin

Answer 23

Inserts into the membrane via a lipophilic tail and Ca2+
Aggregation of daptomycin
Membrane depolarization, leakage of contents and cell death

Question 24

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

Answer 24

B-lactams:

• penicillins
• cephalosporins

Glycopeptides:

• vancomycin
• teicoplanin

Question 25

What’s the mode of action of teicoplanin?

Answer 25

Teicoplanin is a glycopeptide antibiotic produced by fermentation of Streptomyces.
Teicoplanin inhibits the synthesis of cell wall peptidoglycan by interacting with the D-ala-D-ala terminal of the muramylpentapetide (Parenti., 1986)

Question 26

What’s the clinical use of teicoplanin?

Answer 26

used in the prophylaxis and treatment of serious infections caused by Gram-positive bacteria, including MRSA and Enterococcus faecalis.