Examkin

Soru

Zorluk: OrtaInfectious Disease Mechanisms

A 68-year-old man is hospitalized for induction chemotherapy to treat acute myeloid leukemia and subsequently develops severe neutropenia. During his second week of hospitalization, he experiences a fever spike of 39.2°C (102.6°F) and is found to have a central line-associated bloodstream infection. Empiric therapy with cefepime and vancomycin is initiated. Two days later, blood cultures grow *Enterococcus faecium*. Antimicrobial susceptibility testing reveals that the isolate is resistant to ampicillin and vancomycin but susceptible to daptomycin and linezolid. The infectious disease service is consulted, and his antibiotic regimen is modified appropriately. Which of the following best describes the molecular mechanism underlying this organism's resistance to the glycopeptide antibiotic used in his initial empiric regimen?

  1. Replacement of the terminal D-alanine with D-lactate in cell wall precursorsCevap
  2. B
    Expression of a mutated penicillin-binding protein with low drug affinity
  3. C
    Enzymatic adenylation of the antibiotic molecule
  4. D
    Methylation of the 23S rRNA binding site on the 50S ribosomal subunit
  5. E
    Increased expression of transmembrane drug efflux pumps

Cevap

Replacement of the terminal D-alanine with D-lactate in cell wall precursors
Vancomycin is a large glycopeptide antibiotic that functions by tightly binding to the D-alanyl-D-alanine (D-ala-D-ala) terminus of forming peptidoglycan precursors on the extracellular surface of the bacterial cell membrane. This bulky binding physically prevents the transglycosylase and transpeptidase enzymes from incorporating the precursor into the growing cell wall. In Vancomycin-Resistant Enterococcus (VRE), the bacteria have acquired a plasmid (often carrying the *vanA* gene cluster) that encodes enzymes to synthesize D-alanyl-D-lactate (D-ala-D-lac) instead. The substitution of lactate for alanine removes one critical hydrogen-bonding site, drastically reducing vancomycin's affinity for the precursor and allowing cell wall synthesis to proceed uninhibited.

Adım Adım Çözüm

1
Identify the target pathogen and the specific drug referenced in the question.
The pathogen is *Enterococcus faecium*, and the 'glycopeptide antibiotic' used empirically is vancomycin.
Accurate identification is necessary to determine the correct drug-bug resistance pairing.
2
Recall the normal mechanism of action of vancomycin.
Vancomycin normally binds to the D-alanyl-D-alanine (D-ala-D-ala) terminus of peptidoglycan precursors, inhibiting cell wall polymerization.
Understanding the normal target site is required to understand how the bacteria mutates to resist the drug.
3
Determine the molecular mechanism that confers vancomycin resistance in Enterococcus species (VRE).
VRE acquires the *vanA* or *vanB* operon, which reprograms cell wall synthesis to terminate precursors with D-alanyl-D-lactate instead of D-alanyl-D-alanine.
This structural change removes a critical hydrogen bond, reducing vancomycin's binding affinity by a factor of 1,000, allowing the bacteria to survive.

Anahtar Kavram

Vancomycin-resistant Enterococcus (VRE) achieves resistance by acquiring genes that alter peptidoglycan precursors from D-alanyl-D-alanine to D-alanyl-D-lactate, severely decreasing the binding affinity of the glycopeptide antibiotic.
Bu soruyu puanla

Konular

Infectious Disease Mechanisms

Bu konudan daha fazla soru