Examkin

Question

Difficulty: MediumInfectious Disease Mechanisms

A 65-year-old man with a history of a mechanical aortic valve replacement is hospitalized for a 2-week history of low-grade fever, fatigue, and night sweats. Physical examination reveals a new diastolic murmur and splinter hemorrhages on his fingernails. Multiple sets of blood cultures grow Enterococcus faecalis. Antimicrobial susceptibility testing indicates that the isolate is susceptible to ampicillin but exhibits high-level resistance to gentamicin (minimum inhibitory concentration > 500 µg/mL). The infectious disease team determines that the standard ampicillin and gentamicin synergistic combination will not be effective. Which of the following is the most likely molecular mechanism underlying this pathogen's resistance to the aminoglycoside?

  1. Covalent transfer of chemical groups to the antibiotic moleculeAnswer
  2. B
    Alteration of the terminal amino acids in cell wall precursors
  3. C
    Active extrusion of the medication via membrane transport proteins
  4. D
    Enzymatic hydrolysis of the antimicrobial's central cyclic ring
  5. E
    Target site modification through methylation of the ribosomal RNA

Answer

Covalent transfer of chemical groups to the antibiotic molecule
The correct mechanism involves the production of aminoglycoside-modifying enzymes (AMEs). Enterococci possess intrinsic low-level resistance to aminoglycosides due to poor cell wall permeability, but this is overcome by using a cell wall-active agent (like ampicillin) synergistically. However, high-level aminoglycoside resistance (HLAR), defined as an MIC > 500 µg/mL, is typically acquired via mobile genetic elements. This resistance is most frequently conferred by a bifunctional enzyme (AAC(6')-Ie-APH(2'')-Ia) that covalently transfers chemical groups (such as acetyl, adenyl, or phosphoryl groups) to the aminoglycoside molecule. This structural modification sterically hinders the antibiotic, preventing it from binding effectively to the bacterial 30S ribosomal subunit.

Step-by-Step Solution

1
Identify the pathogen and clinical scenario
Enterococcus faecalis endocarditis demonstrating high-level gentamicin resistance (HLAR).
This establishes the target organism and the specific antibiotic resistance profile that needs to be explained.
2
Determine the mechanism of the standard synergistic treatment
Ampicillin inhibits cell wall synthesis, which facilitates the intracellular uptake of the aminoglycoside (gentamicin). Gentamicin then binds to the 30S ribosomal subunit to halt protein synthesis.
Understanding the normal mechanism of action is required to determine how the bacteria evade it.
3
Recall the molecular mechanism of high-level aminoglycoside resistance in enterococci
HLAR is primarily mediated by the production of aminoglycoside-modifying enzymes (AMEs).
Distinguishing between moderate intrinsic resistance (due to poor cell wall permeability) and acquired high-level resistance (due to enzymes) is crucial for accurate diagnosis and management.
4
Identify how aminoglycoside-modifying enzymes function
AMEs function by transferring an acetyl, adenyl, or phosphoryl group to the aminoglycoside molecule, rendering it unable to bind to its ribosomal target.
This specific biochemical alteration directly matches the correct option.

Key Concept

High-level aminoglycoside resistance in enterococci is primarily mediated by the acquisition of genes encoding aminoglycoside-modifying enzymes, which covalently alter the antibiotic.
Rate this question

Topics

Infectious Disease Mechanisms

More questions from this topic