Mechanisms of antimicrobial resistance Flashcards
porins
- how do they mediate antibiotic resistance?
- which bacteria are they imp?
- Found in the outer membrane of gram-negative bacteria (remember there is NO outer membrane in gram-positive bacteria).
- Form hydrophilic channels to allow the selective uptake of hydrophilic antibiotics
Efflux pumps
- how do they mediate antibiotic resistance?
- which bacteria are they imp?
• Can be present in both gram-positive and gram-negative organisms.
Located in bacterial cell membranes → eliminates certain substrates from the bacterial cytoplasm.
Penicillin Binding Proteins (PBPs)
enzymes that perform cross-linking of terminal peptidoglycan of MurNac in peptidoglycan synthesis
- during cross-linking, the last D-alanine of the D-alanine-D-alanine precursor is cleaved off.
How do β-lactam antibiotics work?
β-lactam antibiotics act by irreversibly binding to and inactivating the transpeptidase rxn of PBPs → thereby inhibiting peptide cross-linking and peptidoglycan synthesis.
Which bacteria has intrinsic PBP altered properties?
MRSA - makes it highly resistant to PCNs
How bacteria become resistant to β-lactams:
- Modifying the drug—through enzymatic destruction of β-lactams by β-lactamases
- Modifying the target—through production of altered penicillin-binding proteins (PBPs) with low affinity for β-lactam binding.
- Preventing drug-target interaction—both porin channel mutations and drug efflux mechanisms can increase resistance to β-lactams by preventing β-lactam interaction with the PBPs.
β-lactamase
enzymes that inactivate β-lactam antibiotics by splitting the amide bond of the β-lactam ring → thereby protect the activity of penicillin binding proteins.
Narrow spectrum beta-lactamase
bla gene on staph
TEM-1 gene on E.coli
SHV-1 gene on Kleb
–> all resistant to PCN and amp
What is ampC and where is it found?
ampC encodes cephalosporinase (a Beta-lactamase)
found on chromosomes of Gram - rods
Enterobacter, Pseudomonas, ect
Enterobacter w/ ampC in its genome, in normal inducible state is resistant to which drugs?
Amp
Cefazolin (1st)
________
sensitive to all other drugs
- note: Ampicillin turns on ampC (a beta lactamase) so it makes bacteria w/ ampC resistant to itself
Enterobacter DEVELOPS ampC mutation, expression is constitutive, this makes it resistant to which drugs?
All drugs except carbapenems (ertapenems)
Ertapenem is not degraded by ampC, so still sensitive
If an organism has inducible ampC, what do you do?
you want to be safe when treating organisms that house inducible ampC, you need to remember which organisms have it and then use a carbapenem
(one step from full resistance to all but carbapenems)
mecA gene
• Seen only in staphylococci
Encodes for a modified, low affinity penicillin-binding protein (PBP) called PBP2a → confers resistance to all β-lactam agents
□ When present in S. aureus, it is classified as “methicillin-resistant” S. aureus, otherwise known as MRSA
Mosaic PBPs
• Seen mainly in Streptococcus pneumoniae and Neisseria gonorrhoeae.
These bacteria can “pick up” pieces of genetic material (via transformation) from other bacteria and swap them with similar pieces of DNA in their own chromosome
VRE
○ Genes encoding resistance vanA and vanB –>encodes enzymes that substitute D-ala-D-ala to D-ala-D-lac. This new precursor has reduced affinity to vancomycin.
