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Difficulty: HardInfectious Disease Mechanisms

A 71-year-old man with a history of a mechanical aortic valve replacement presents to the hospital with two weeks of low-grade fever, fatigue, and night sweats. Physical examination reveals a new early diastolic murmur and small, tender erythematous nodules on the pads of his fingers. Transesophageal echocardiography demonstrates an oscillating 0.8-cm vegetation on the prosthetic valve. Multiple blood cultures grow *Enterococcus faecalis*. Susceptibility testing indicates the isolate is susceptible to ampicillin but demonstrates high-level resistance to gentamicin. Consequently, the planned synergistic regimen of ampicillin and gentamicin is abandoned, and he is treated with ampicillin and ceftriaxone. Which of the following best describes the molecular mechanism responsible for this isolate's high-level resistance to gentamicin?

  1. Covalent modification of the antimicrobial molecule via enzymatic transfer of functional groupsAnswer
  2. B
    Target-site alteration of the 30S ribosomal subunit via chromosomal mutation
  3. C
    Active cellular extrusion of the drug via upregulated transmembrane efflux pumps
  4. D
    Substitution of a terminal amino acid in cell-wall structural precursor peptides
  5. E
    Decreased intracellular drug accumulation secondary to outer membrane porin deletion

Answer

The correct answer is covalent modification of the antimicrobial molecule via enzymatic transfer of functional groups.
The correct answer is covalent modification of the antimicrobial molecule via enzymatic transfer of functional groups. Enterococci exhibit intrinsic low-level resistance to aminoglycosides due to their thick peptidoglycan cell wall, which limits drug uptake. This intrinsic barrier is typically overcome by combining the aminoglycoside with a cell-wall active agent (e.g., ampicillin, penicillin, or vancomycin) to achieve synergistic bactericidal activity. However, some enterococci acquire high-level aminoglycoside resistance (HLAR), which abolishes this synergistic effect. For gentamicin, HLAR is almost exclusively mediated by the acquisition of mobile genetic elements (plasmids or transposons) encoding aminoglycoside-modifying enzymes (AMEs). Specifically, a bifunctional enzyme, AAC(6')-Ie-APH(2'')-Ia, covalently alters the gentamicin molecule via acetylation and phosphorylation. This structural modification severely reduces the drug's binding affinity for its target on the bacterial 30S ribosomal subunit.

Step-by-Step Solution

1
Analyze the clinical scenario and the specific pathogen.
The patient has infective endocarditis caused by Enterococcus faecalis.
Identifying the pathogen is the first step to determining species-specific resistance mechanisms.
2
Identify the pharmacological principle underlying the treatment regimen.
Standard therapy involves a cell-wall active agent (ampicillin) plus an aminoglycoside (gentamicin) to achieve bactericidal synergy.
Enterococci have intrinsic low-level resistance to aminoglycosides due to their thick peptidoglycan wall; ampicillin facilitates aminoglycoside cellular entry.
3
Determine the molecular basis for the high-level resistance noted in the laboratory report.
High-level aminoglycoside resistance (HLAR) to gentamicin abolishes synergy and is mediated by plasmid-encoded aminoglycoside-modifying enzymes (AMEs).
AMEs covalently attach functional groups (e.g., acetyl, adenyl, phosphoryl groups) to the drug, neutralizing its ability to bind the bacterial ribosome.

Key Concept

High-level aminoglycoside resistance (HLAR) to gentamicin in Enterococcus species is mediated by plasmid-encoded aminoglycoside-modifying enzymes that covalently alter the drug structure, destroying its ability to bind to the 30S ribosomal subunit.
Estimated Time:1m 30s
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Topics

Infectious Disease Mechanisms

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