Mechanisms of Antibiotic Resistance (complete) Flashcards
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
Describe the mechanisms of resistance to quinolones
- Target DNA gyrase/topoisomerase IV => lethal DNA strand breaks
Resistance:
- Modify target: accumulate many point mutations in those enzymes
Describe the mechanism of erm-mediated resistance
- Can be inducible or on all the time (macrolides do this)
- While on therapy, you can develop a mutation that shifts from inducible to on all the time
How is the mechanism of erm-mediated resistance related to clindamycin resistance?
- Clindamycin can cause a switch fro inducible to constitutive
- Clindamycin is sensitive to inducible erm but obviously not to constitutive erm
- Used to determine method of resistance of specific staphs
What is the utility of the D-test as it relates to the mechanism of erm-mediated resistance?
- Done when you’re resistant to erythromycin and sensitive to clindamycin
- If D-test is positive (have inducible erm), you don’t want to use clindomycin or erythromycin
- If negative (efflux pump present), then you can use clindamycin, still no macrolides (erythromycin)
Why is E. Coli naturally resistant to penicillin but sensitive to ampicillin?
Porins!
Why is mycoplasma resistant to all beta-lactams?
No cell wall!
What are 2 types of bacteria that are similar to E. Coli? What type of bacteria are they?
1) Enterobacter
2) Klebsiella
G(-) rods
How does strep pneumo become resistant to beta-lactams?
- Through an altered PBPs
IMPORTANT:
NO STREPS HAVE BETA-LACTAMASES!!!!!
