Mechanisms of Antibiotic Resistance (complete) Flashcards
(32 cards)
What is intrinsic resistance?
- The bug just happens to be resistant
- Was this way before antibiotics were even invented
Pseudomonas is a great example
What is acquired resistance?
- It’s acquired! No shit sherlock
- Developed through mutations, new genes — bacteria can figure shit out
Important: resistance is a multi-step process and most bacteria will not be resistant after one mutation — but they will with a new gene
What are the broad categories of antibiotic resistance?
1) Inactivate/modify drug
2) Alter the antibacterial target
3) Reduce the ability of the drug to reach the target
How do porins mediate antibiotic resistance? For which bacteria is this important?
- Porins found in g(-) bacteria (they have an outer membrane)
- Antibiotic must go through the channel to its job
- Bacteria alter structure of porin channels to resist teh antibiotic
How do efflux pumps mediate antibiotic resistance? For which bacteria is this important?
- Found in g(+) and g(-)
- Can be specific or general (either cause 1 antibiotic to be pumped out of cell or more)
- Can prevent antibiotic from doing its thang — can’t alter whatever it’s designed to alter in the cell
Describe the structure and building of peptidoglycan as it relates to the mechanisms of activity of beta-lactams and vancomycin.
Structure: backbone of 2 alternating sugars, cross-linked
Formation: adding precursors —» cross-linking then driven by cleavage of terminal stem-peptide AAs (enzymes involved here are called PBPs)
Describe how changes in peptidoglycan synthesis may result in resistance to these agents
- Some antibiotics target specific steps in peptidoglycan synthesis
- Overall prevents cell wall synthesis of bacteria
Describe how beta-lactams work
- Bind to and inactivated PBPs
- it’s irreversible
- Prevents peptidoglycan formation
THINK: Stage 3!!!
Describe how bacteria become resistant to beta-lactams
1) Modify drug => w/ beta-lactamases
2) Modify target => alter PBPs
Example of altered PBPs: MRSA
Describe the spectrum of activity of “narrow spectrum” beta-lactamases.
- Hydrolyze PCN-type antibiotics
- Not much activity against cephalosporins
- Found in g(+) and g(-) bacteria
- Encoded on chromosome or a plasmid!
Which bacteria house “narrow spectrum” beta-lactamases?
1) S. aureus (resistant to PCNs, ampicillin) => plasmid
2) E. Coli TEM1 (amp) => plasmid
3) Klebsiella (amp) => chromosome
Describe the spectrum of activity for ESBLs
- Extended Spectrum Beta-Lactamases
- Almost all found on plasmids (highly mobile)
- Found in g(-) rods
- Resistant to PCNs and most cephalosporins (aka that’s why it’s EXTENDED)
Which bacteria house ESBLs?
- Mutants of TEM1, TEM2, SHV1
- E.coli and Klebs. pneumo love to pick up the plasmids w/ these point mutations
Describe the spectrum of activity for ampC?
- Found in the chromosomes! — inducible or on allll the time
- in certain g(-) rods
- Resistance to PCNs and cephalosporins
- CANNOT be inhibited by beta-lactamase inhibitors (e.g. tazobactams)
Which bacteria house ampC?
- Pseudomonas
- Enterobacter
Describe the spectrum of activity for carbapenemases.
- Developed b/c everyone was usually carbapenems to treat ampC and ESBL bacteria (b/c of resistance to other drugs)
- Resistant to all beta-lactams
- Found on plasmids
Which bacteria house carbapenemases?
- KPC: Kleb pneumo carbapenemase
- NDM-1: New Delhi metallo-beta-lactamase
Describe the regulation of ampC expression
- Expression is the key part of AmpC
- Normally => low level of expression, but induced by specific beta-lactamas
- Therapy causes it to switch from inducible to constitutive (on all the time)
- Mutation causes inducer to be present all the time as a leftover part of peptidoglycan formation
What are the different ways that PBPs may be altered that lead to beta-lactam resistance?
- Mutation of existing genes
- Acquiring new PBP genes
- Acquiring new pieces of PBP genes
Which bacteria house altered PBPs?
- Staph species (s. aureus, MRSA) — new gene
- Strep pneumo — new pieces
- N. gonnhoroeae — new pieces
How does Vancomycin work?
- Targets peptidoglycan precursor => binds to D-ala-D-ala
- Inhibits incorporation of precursor w/ PD => disrupts CW synthesis
THINK: STAGE 2
How do bacteria become resistant to Vancomycin?
- G(-) rods intrinsically resistant
- Modifying the target (changes the D-ala-D-ala –» D-ala-D-lactate)
- Seen in enterococcus
Describe the mechanisms of resistance to macrolides
- Macrolides target RNA => prevent peptide elongation
Resistance mechanisms:
- Modify target => erm gene (changes, dimethylates ribosome)
- Prevent drug-target interaction => drug efflux, msr gene
- S. aureus can become resistant to Erythromycin in these ways
Describe the mechanisms of resistance to aminoglycosides
- Modifies the drug: acetylation, nucleotidylation, phosphorylation
- Get an enzyme that does one of the above
