Antimicrobial Resistance Flashcards
Describe the difference between intrinsic and acquired antibiotic resistance and list ways a bacterium may acquire antibiotic resistance.
Intrinsic resistance: Natural properties of bacteria that confer resistance (e.g. porins, lack of a cell wall).
Acquired resistance: Resistance that develops by genetic mutation or acquisition of new genes. (e.g. plasmids, transposons, bacteriophages)
Describe the broad categories of antibiotic resistance
- Inactivate or modify target
- Alter the microbial target
- Prevent drug and target from meeting (efflux)
Describe how porins and efflux pumps can mediate antibiotic resistance and for which types of drugs and for which types of bacteria they are important.
Porins: gram negative bacteria only, allows for the passage of antibiotics… changes to configuration and/or number of porins can have effects upon antibiotic uptake.
Efflux pumps: gram + and gram - bacteria, efflux pumps can prevent drug/target interaction by pumping substrates from bacterial cytoplasm, can result in multi-drug class resistance.
Describe the structure and building of peptidoglycan as it relates to the mechanisms of activity of beta-lactams and vancomycin and how changes in peptidoglycan synthesis may result in resistance to these agents.
Peptidoglycan is composed of:
1) a backbone of two alternating sugars (GlcNAc and MurNAc)
2) A chain of four amino acids
3) a peptide bridge that cross-links the chains.
Peptidoglycan is formed by the addition of subunits (precursors of GlcNAc and MurNAc) that are assembled in the cytoplasm and transported through the cytoplsmic membrane to the cell surface. Subsequent amino acid cross-linking (transpeptidation) is driven by cleavage of the terminal stem-peptide amino acid. Transglycosylation is joining of the suggar molecules.
transglycosylation and transpeptidation are accomplished by Penicillin Binding Proteins (PBPs)
Describe how beta-lactams work and how bacteria can become resistant to beta-lactams.
Beta lactams irreversibly bind to and inactivate the transpeptidase rxn of PBPs, thereby inhibiting peptide cross-linking, and thus, peptidoglycan synth.
Bacteria become resistant to Beta lactams via :1)Beta lactamases
2) Production of altered PBPs
3) Porin channel mutations and drug efflux mechanisms that prevent beta-lactam interaction with PBPs
Describe the spectrum of activity and list bacteria that may house “narrow-spectrum” beta-lactamases.
Certain beta-lactamases had a narrow spectrum of activity to beta-lactams.
Bacteria that may house narrow spectrum beta-lactamase: S. Auereus, E. Coli TEM 1, Klebs. pneumo
Define an ESBL, know which bacteria may express them, and what class of beta-lactam antibiotics may still be used against organisms housing an ESBL
ESBLs are beta lactamases that mutated from TEM-1, TEM-2, and SHV-1 genes, which are capable are degrading more beta-lactams than the previous narrow beta-lactamases.
Bacteria that express ESBLs are most commonly found in Klebs. pneumo and E. Coli.
Can be inhibited by clavulanic acid or carbapenems
Describe the regulation of ampC expression, know which bacteria house ampC in their chromosome, and know what class of beta-lactams may be used against organisms that have ampC.
AmpC encodes for a beta lactamase that is capable of hydrolyzing pcns, all 1st, 2nd and 3rd gen cephalsporins, and it’s activity isn’t inhibited by beta-lactamase inhibitors.
ampC is chromosomally located, and can be expressed constitutively or inducibly. Normally only trace amounts are expressed, however, mutations can cause it to be expressed constituitively.
It is found in certain gram neg. rods, such as enterobacter and pseudomas and serratia.
Carbapenems can be used against organisms that have ampC.
Describe KPC and NDM-1 and know which bacteria may house these resistance determinants.
KPC and NDM-1 are plasmid-mediated carbapenamases.
KPC hydrolyzes all carbapenams and all other beta-lactams.
NDM-1 hydrolyzes all beta-lactams except for aztrennam.
Bacteria that may house these are Klebsiella and E. coli (rarely in NDM-1).
Describe the different ways that PBPs may be altered that lead to beta-lactam resistance and which bacteria may house altered PBPs.
Bacteria can either produce an altered PBP by modification of existing genes, or the acquisition of new PBP genes (more important mechanism).
Bacteria that often have this include
Staphylococci spp (mecA-PBP2a i.e. MRSA)
S. pneumoiae
Entercoccus faecium.
Describe the organisms and mechanisms associated with vancomycin resistance.
1) Modifying the target: almost exclusively in enterococcus spp through the acquisition of a plasmid that carries a gene that will change the terminal five-memeber peptide that hangs off of the MurNAc sugar, making it unrecognizable to Vanco. (turns D-ala–D-ala to D-ala–D-lactate
2) Preventing drug-target interaction: in S. aureus there are thickened peptidoglycan cell walls with incomplete crosslinking. Vanco binds to excess D-ala-D-ala sites in cell wall, leaving decreased drug to bind to the precursor PG molecule.
Distinguish the mechanisms of antibiotic resistance between Enterococcus faecium and Enterococus faecalis.
Enterococcus faecium: mutatation or overexpression of PBP5- a PBP will low affinity for B-lactam—> is highly resistant to ampicillin
Entercoccus faecalis: Beta-lactamase transfered via plasmid
Describe how quinolones work and how resistance to these agents develops.
Quinolones target enzymes DNA gyrase and Topoisomerase IV; they trap the enzymes in a drug-enzyme-DNA complex, leading to lethal DNA strand breaks.
Mechanisms of resistance:
1) Modifying the drug: rare, e.g. plasmid can acetylate ciprofloxacin.
2) Modifying the target: accumulation of point mutations in DNA gyrase and/or topoisomerase IV
3) Preventing drug-target ineraction: drug efflux mechanisms can prevent interaction with DNA gyrase/topoisomerase IV
Describe how macrolides work and how resistance to these agents develops.
Macrolides work by binding to a domain of the 23S ribosomal RNA that is a component of the 50S subunit of the bacterial ribosome… Prevents peptide chain elongation.
Mechanisms of resistance:
Modifying the target: Demethylation of the 23S rRNA (erm gene)
Modifying drug-target interaction: efflux pumps (msr gene)
Describe the mechanism of erm-mediated resistance and its relation to clindamycin resistance and understand how to interpret results from the D-test.
Ribosome demethylation is performed by a methylase encoded by erm. Erm gene is either inducible or constituitive.
Macrolides and Clindamycin bind to an adenine residue in the ribosome. If erm is expressed, bacteria will be resistant to both macrolides and clindamycin. Only macrolides will induce expression of erm.
D-test will show whether or not an efflux system is present. Positive D test will show resistance to clindamycin due to inducible erm expression. Clindamycin should not be used b/c it might select for mutants that constituitively produce erm-encoded methylase.
