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Difficulty: Very hardInfectious Disease Mechanisms

A 34-year-old man with a history of intravenous drug use is admitted to the hospital with fever, chills, and pleuritic chest pain. Blood cultures grow *Staphylococcus aureus* resistant to oxacillin but susceptible to vancomycin. Echocardiography reveals a 1.4-cm mobile vegetation on the tricuspid valve. He is started on intravenous vancomycin. Over the next two weeks, the patient remains persistently febrile, and surveillance blood cultures continue to yield *S. aureus*. Susceptibility testing shows the minimum inhibitory concentration (MIC) for vancomycin has increased from 1.0 to 4.0 mcg/mL. The patient's antimicrobial regimen is changed to a cyclic lipopeptide agent that binds to the bacterial cell membrane in a calcium-dependent manner, leading to rapid depolarization and cell death. The patient shows initial clinical improvement, but four weeks later, he presents again with fever and recurrent bacteremia with the same organism. Susceptibility testing now reveals resistance to the newly added cyclic lipopeptide agent. Which of the following molecular events best explains the organism's acquired resistance to the second-line antimicrobial agent?

  1. Addition of L-lysine to phosphatidylglycerol within the cell membraneAnswer
  2. B
    Reprogramming of peptidoglycan termini from D-alanyl-D-alanine to D-alanyl-D-lactate
  3. C
    Synthesis of a thickened cell wall with increased numbers of decoy binding sites
  4. D
    Point mutation in the 23S ribosomal RNA of the 50S subunit
  5. E
    Enzymatic inactivation of the drug via a plasmid-encoded acetyltransferase

Answer

Addition of L-lysine to phosphatidylglycerol within the cell membrane
The patient initially failed vancomycin therapy due to reduced susceptibility (Vancomycin-Intermediate S. aureus, or VISA) and was subsequently switched to daptomycin. Daptomycin is a cyclic lipopeptide antibiotic that inserts into the bacterial cell membrane in a calcium-dependent manner, causing rapid depolarization, potassium efflux, and cell death. Resistance to daptomycin in S. aureus typically occurs through gain-of-function mutations in the multiple peptide resistance factor (mprF) gene. The MprF protein is an enzyme that adds positively charged L-lysine molecules to membrane phosphatidylglycerol, creating lysyl-phosphatidylglycerol. This modification neutralizes the normally negative net surface charge of the bacterial membrane, shifting it to a more positive charge. Because the active daptomycin-calcium complex is also positively charged, the altered membrane electrostatically repels the drug, preventing its insertion and subsequent cell death.

Step-by-Step Solution

1
Identify the cause of the initial treatment failure.
The vancomycin MIC increased to 4.0 mcg/mL, indicating the development of Vancomycin-Intermediate S. aureus (VISA).
Recognizing the initial failure helps establish the context for the subsequent drug switch.
2
Identify the second-line antimicrobial agent based on its mechanism of action.
The agent is daptomycin, a cyclic lipopeptide that causes calcium-dependent membrane depolarization.
Knowing the specific drug is necessary to determine its unique resistance mechanisms.
3
Determine the molecular mechanism of resistance to daptomycin in S. aureus.
Resistance occurs via mutations in the mprF gene, leading to the addition of L-lysine to phosphatidylglycerol.
This specific alteration changes the membrane charge, directly answering the question.

Key Concept

The primary mechanism of daptomycin resistance in Staphylococcus aureus involves mutations in the mprF gene, which alter the cell membrane charge to repel the calcium-bound drug complex.
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Topics

Infectious Disease Mechanisms

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