Lecture 16 - Antimicrobial Mechanisms and Resistance II

Question 1

When are anti-membrane antimicrobials not used as a last resort?

Answer 1

In antifungal cases

Question 2

Bonds linking rows of peptidoglycan

Answer 2

L-Lysine - Penta-glycine - D-Alanine

Question 3

Polysaccharides making up peptidoglycan

Answer 3

N-acetylmuramic acid

N-acetylglucosamine

Question 4

How are peptidoglycans cross-linked?

Answer 4

Penta-glycine displaces 2nd D-Ala on L/D polypeptide.

This is catalysed by transpeptidase

Question 5

How is peptidoglycan assembled?
1)
2)

Answer 5

1) Building blocks are immobilised on the inside of the cell membrane
2) Assembled building blocks are flipped onto cell exterior

Question 6

Other names for transpeptidases

Answer 6

Endopeptidases

Carboxypeptidases

Question 7

When was vancomycin first used?

Answer 7

In the 1950s, when Staph aureus began to be resistant to beta-lactams.

Question 8

What is MRSA?

Answer 8

Methicillin-resistant staph aureus

Question 9

What does methicillin resistance signify?

Answer 9

Resistance to almost every other beta lactam

Question 10

Which type of antimicrobial is vancomycin?

Answer 10

Glycopeptide

Question 11

How does vancomycin work?

Answer 11

Binds directly to D-ala - D-ala on peptidoglycan precursor

Question 12

Shape of vancomycin molecule

Answer 12

Very large, very charged

Question 13

Why can’t vancomycin be used against G- bacteria?

Answer 13

Because it is very large and highly-charged

Can’t pass through thicker cell wall.

Question 14

Which bacteria is vancomycin useful against?

Answer 14

Staph aureus

Question 15

Bacteria innately resistant to vancomycin

Answer 15

Gram-, enterococci

Question 16

Why are enterococci resistant to vancomycin?

Answer 16

D-ala - D-ala is replaced by D-ala - D-lac

Question 17

Danger of VRE

Answer 17

Enterococci aren’t pathogenic, but are promiscuous in sharing plasmids, on which vancomycin resistance could be encoded

Question 18

VISA

Answer 18

Vancomycin intermediate-resistant staph aureus

Question 19

Mechanism of staph aureus partial vancomycin resistance

Answer 19

Produce more peptidoglycan.
As vancomycin inhibits peptidoglycan directly, if there is enough peptidoglycan, there can remain enough to perform function after vancomycin has been used up.

Question 20

Issue with treating VISA

Answer 20

Greater amount of peptidoglycan can be overwhelmed with more vancomycin, though vancomycin is toxic in higher doses, so this can be dangerous

Question 21

How do beta-lactams work?

Answer 21

1) Bind to transpeptidases
2) Transpeptidases can’t hydrolyse the beta-lactam ring
3) Peptidoglycan can’t be assembled

Question 22

What do transpeptidases hydrolyse?

Answer 22

CONH bond between D-ala - D-ala

Question 23

Effect on bacteria of beta-lactams

Answer 23

Cell wall is weakened

Bacterial cytoplasm is hypertonic to surrounding tissue fluid, so bacteria swell

Question 24

Action of beta-lactamases

Answer 24

Hydrolyse a bond in beta-lactam ring

From O=C-N to O=C-OH NH

Question 25

Resistance to beta lactams 1) 2)

Answer 25

1) Beta-lactamase | 2) Altered penicillin-binding proteins

Question 26

Why does the bacterial spectrum of beta-lactam antibiotics vary? 1) 2) 3)

Answer 26

1) Different bacteria have different penicillin-binding proteins 2) Accessibility of antibiotic to penicillin-binding protein varies 3) Antibiotics have different susceptibilities to beta-lactamases

Question 27

Clavulanic acid 1) 2) 3)

Answer 27

1) A beta-lactam antibiotic 2) Binds to beta-lactamases, beta-lactamases can't hydrolyse clavulanic acid 3) A suicide inhibitor of beta-lactamases

Question 28

Clavulanic acid uses

Answer 28

Used to inhibit beta-lactamases | Ineffective if used by itself, but effective if combined with another beta-lactam, EG: amoxycillin

Question 29

How is clavulanic acid administered?

Answer 29

1) Equal parts clavulanic acid, amoxycillin. 2) As clavulanic acid and amoxycillin are processed in very similar ways, they are both delivered to the site of infection.

Question 30

Co-Amoxyclav

Answer 30

Clavulanic acid and amoxycillin treatment

Question 31

What is Pseudomonas aeruginosa intrinsically resistant to?

Answer 31

Beta-lactams

Question 32

Why is Pseudomonas resistant to beta-lactams?

Answer 32

Has a beta-lactamase gene in its chromosome | Probably used to help form cell wall

Question 33

Beta-lactams that Pseudomonas is susceptible to

Answer 33

Carbenicillin | Ticarcillin

Question 34

Effect of clavulanic acid on Pseudomonas

Answer 34

Nothing. | Clavulanic acid can be hydrolysed by Pseudomonas chromosomally-encoded beta-lactamase

Question 35

How can Pseudomonas become resistant to carbenicillin and ticarcillin?

Answer 35

If it acquires a beta-lactamase plasmid

Question 36

How can a Pseudomonas with a beta-lactamase plasmid be treated?

Answer 36

With ticarcillin and clavulanic acid. Pseudomonas is susceptible to ticarcillin, but beta-lactamase plasmid degrades it. Clavulanic acid inhibits plasmid beta-lactamase.

Question 37

Number of beta-lactamases

Answer 37

Used to be under 10. | With widespread use of beta-lactams, now over 500

Question 38

Gene encoding altered penicillin-binding proteins

Answer 38

MecA

Question 39

What does MecA encode?

Answer 39

Altered penicillin-binding protein | Is a transpeptidiase that doesn't bind beta-lactams

Question 40

Why is ampicillin more orally available than penicillin G?

Answer 40

Ampicillin is more lipophilic

Question 41

New Delhi beta-lactamase

Answer 41

Destroys most modern beta-lactams | Quickly transferred between bacteria on plasmid

Question 42

New beta-lactamase that can destroy most beta lactams

Answer 42

New-Delhi beta-lactamase