Examkin

Soru

Zorluk: OrtaInfectious Disease Mechanisms

A 68-year-old man is hospitalized for the management of native-valve infective endocarditis. Blood cultures obtained on admission grow methicillin-resistant *Staphylococcus aureus* (MRSA). The patient is started on intravenous vancomycin. On hospital day 5, repeat blood cultures remain positive, and the vancomycin minimum inhibitory concentration (MIC) for the isolate is reported as 2 mcg/mL. Following an infectious disease consultation, his antimicrobial regimen is changed to intravenous daptomycin. The patient's clinical status initially improves, and clearance of bacteremia is documented. However, on hospital day 24, he develops recurrent high-grade fevers and chills. Repeat blood cultures once again grow MRSA. Susceptibility testing of the new isolate demonstrates a daptomycin MIC of 8 mcg/mL, indicating resistance. Which of the following molecular changes most likely occurred in this organism to confer resistance to the current antibiotic?

  1. Addition of a basic amino acid to membrane phospholipidsCevap
  2. B
    Alteration of cell wall precursor termini to D-alanyl-D-lactate
  3. C
    Synthesis of a novel cell wall transpeptidase with reduced drug affinity
  4. D
    Overexpression of a transmembrane efflux pump
  5. E
    Enzymatic inactivation of the drug via acetylation

Cevap

Addition of a basic amino acid to membrane phospholipids
The correct answer accurately describes the mechanism of daptomycin resistance in Staphylococcus aureus. Daptomycin is a lipopeptide antibiotic that requires calcium to insert into the Gram-positive cell membrane. Resistance most frequently arises from a mutation in the mprF (multiple peptide resistance factor) gene. This mutation increases the synthesis of lysyl-phosphatidylglycerol by transferring the positively charged amino acid L-lysine to phosphatidylglycerol. The increased concentration of positively charged lipids on the outer leaflet of the cell membrane creates an electrostatic repulsion against the active daptomycin-calcium complex, thereby preventing its insertion and subsequent cell depolarization.

Adım Adım Çözüm

1
Identify the patient's clinical scenario and the specific antimicrobial failure.
The patient developed recurrent MRSA bacteremia while on daptomycin therapy, and the new isolate is definitively resistant to daptomycin.
Establishing the specific drug failure focuses the inquiry on mechanisms of daptomycin resistance rather than baseline methicillin resistance.
2
Recall the mechanism of action of daptomycin.
Daptomycin is a cyclic lipopeptide that complexes with calcium to insert into the Gram-positive bacterial cell membrane, causing rapid depolarization and cell death.
Understanding the target (the cell membrane) is essential to deducing how the bacteria evade the drug.
3
Determine the specific molecular mechanism of daptomycin resistance in Staphylococcus aureus.
Resistance primarily occurs via mprF gene mutations, which upregulate the transfer of the basic (positively charged) amino acid lysine to membrane phosphatidylglycerol.
This molecular change increases the net positive charge of the cell envelope, electrostatically repelling the positively charged daptomycin-calcium complex.

Anahtar Kavram

Daptomycin resistance in Staphylococcus aureus is typically mediated by mprF gene mutations, which lead to the addition of lysine (a positively charged basic amino acid) to membrane phospholipids. This increases the net positive charge of the bacterial cell membrane, repelling the drug.
Bu soruyu puanla

Konular

Infectious Disease Mechanisms

Bu konudan daha fazla soru