Lecture 16 - Antimicrobial Mechanisms and Resistance II Flashcards
When are anti-membrane antimicrobials not used as a last resort?
In antifungal cases
Bonds linking rows of peptidoglycan
L-Lysine - Penta-glycine - D-Alanine
Polysaccharides making up peptidoglycan
N-acetylmuramic acid
N-acetylglucosamine
How are peptidoglycans cross-linked?
Penta-glycine displaces 2nd D-Ala on L/D polypeptide.
This is catalysed by transpeptidase
How is peptidoglycan assembled?
1)
2)
1) Building blocks are immobilised on the inside of the cell membrane
2) Assembled building blocks are flipped onto cell exterior
Other names for transpeptidases
Endopeptidases
Carboxypeptidases
When was vancomycin first used?
In the 1950s, when Staph aureus began to be resistant to beta-lactams.
What is MRSA?
Methicillin-resistant staph aureus
What does methicillin resistance signify?
Resistance to almost every other beta lactam
Which type of antimicrobial is vancomycin?
Glycopeptide
How does vancomycin work?
Binds directly to D-ala - D-ala on peptidoglycan precursor
Shape of vancomycin molecule
Very large, very charged
Why can’t vancomycin be used against G- bacteria?
Because it is very large and highly-charged
Can’t pass through thicker cell wall.
Which bacteria is vancomycin useful against?
Staph aureus
Bacteria innately resistant to vancomycin
Gram-, enterococci
Why are enterococci resistant to vancomycin?
D-ala - D-ala is replaced by D-ala - D-lac
Danger of VRE
Enterococci aren’t pathogenic, but are promiscuous in sharing plasmids, on which vancomycin resistance could be encoded
VISA
Vancomycin intermediate-resistant staph aureus
Mechanism of staph aureus partial vancomycin resistance
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.
Issue with treating VISA
Greater amount of peptidoglycan can be overwhelmed with more vancomycin, though vancomycin is toxic in higher doses, so this can be dangerous
How do beta-lactams work?
1) Bind to transpeptidases
2) Transpeptidases can’t hydrolyse the beta-lactam ring
3) Peptidoglycan can’t be assembled
What do transpeptidases hydrolyse?
CONH bond between D-ala - D-ala
Effect on bacteria of beta-lactams
Cell wall is weakened
Bacterial cytoplasm is hypertonic to surrounding tissue fluid, so bacteria swell
Action of beta-lactamases
Hydrolyse a bond in beta-lactam ring
From O=C-N to O=C-OH NH
Resistance to beta lactams
1)
2)
1) Beta-lactamase
2) Altered penicillin-binding proteins
Why does the bacterial spectrum of beta-lactam antibiotics vary?
1)
2)
3)
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
Clavulanic acid
1)
2)
3)
1) A beta-lactam antibiotic
2) Binds to beta-lactamases, beta-lactamases can’t hydrolyse clavulanic acid
3) A suicide inhibitor of beta-lactamases
Clavulanic acid uses
Used to inhibit beta-lactamases
Ineffective if used by itself, but effective if combined with another beta-lactam, EG: amoxycillin
How is clavulanic acid administered?
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.
Co-Amoxyclav
Clavulanic acid and amoxycillin treatment
What is Pseudomonas aeruginosa intrinsically resistant to?
Beta-lactams
Why is Pseudomonas resistant to beta-lactams?
Has a beta-lactamase gene in its chromosome
Probably used to help form cell wall
Beta-lactams that Pseudomonas is susceptible to
Carbenicillin
Ticarcillin
Effect of clavulanic acid on Pseudomonas
Nothing.
Clavulanic acid can be hydrolysed by Pseudomonas chromosomally-encoded beta-lactamase
How can Pseudomonas become resistant to carbenicillin and ticarcillin?
If it acquires a beta-lactamase plasmid
How can a Pseudomonas with a beta-lactamase plasmid be treated?
With ticarcillin and clavulanic acid.
Pseudomonas is susceptible to ticarcillin, but beta-lactamase plasmid degrades it.
Clavulanic acid inhibits plasmid beta-lactamase.
Number of beta-lactamases
Used to be under 10.
With widespread use of beta-lactams, now over 500
Gene encoding altered penicillin-binding proteins
MecA
What does MecA encode?
Altered penicillin-binding protein
Is a transpeptidiase that doesn’t bind beta-lactams
Why is ampicillin more orally available than penicillin G?
Ampicillin is more lipophilic
New Delhi beta-lactamase
Destroys most modern beta-lactams
Quickly transferred between bacteria on plasmid
New beta-lactamase that can destroy most beta lactams
New-Delhi beta-lactamase
