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Difficulty: MediumInfectious Disease Mechanisms

A 28-year-old man comes to the clinic with a painful, swollen, and red area on his right forearm. The lesion has been progressively worsening over the past 3 days. He has a history of injection drug use. Physical examination reveals a 4-cm erythematous, fluctuant nodule with surrounding induration and warmth. The abscess is incised and drained, yielding thick, purulent material. A Gram stain of the exudate shows Gram-positive cocci in clusters. The patient is prescribed oral cephalexin and discharged. Two days later, he returns to the emergency department with expanding erythema extending up to his elbow, worsening pain, and a new fever of 38.6°C (101.5°F). Subsequent culture results confirm the presence of an organism that is resistant to oxacillin. Which of the following best describes the molecular mechanism responsible for this pathogen's resistance to the initial outpatient antibiotic therapy?

  1. Acquisition of a mobile genetic element encoding a variant peptidoglycan transpeptidaseAnswer
  2. B
    Plasmid-mediated production of an enzyme that hydrolyzes the cyclic amide bond of the antibiotic
  3. C
    Chromosomal upregulation of a transmembrane complex that actively expels the drug
  4. D
    Downregulation of outer membrane channel proteins leading to decreased intracellular drug accumulation
  5. E
    Enzymatic methylation of a ribosomal RNA binding site

Answer

Acquisition of a mobile genetic element encoding a variant peptidoglycan transpeptidase
The correct answer accurately describes the mechanism of resistance in Methicillin-Resistant Staphylococcus aureus (MRSA). The patient's purulent abscess and Gram stain showing Gram-positive cocci in clusters are diagnostic of Staphylococcus aureus. The failure of cephalexin (a beta-lactam) and documented resistance to oxacillin confirm MRSA. MRSA arises when strains acquire the Staphylococcal cassette chromosome mec (SCCmec), a mobile genetic element that carries the mecA gene. This gene encodes penicillin-binding protein 2a (PBP2a), which is a variant peptidoglycan transpeptidase. Because PBP2a has a very low binding affinity for beta-lactam antibiotics, the bacteria can successfully continue cross-linking peptidoglycan and synthesizing its cell wall even when therapeutic concentrations of beta-lactams are present.

Step-by-Step Solution

1
Identify the likely pathogen based on the clinical presentation and Gram stain.
The patient has a purulent skin and soft tissue infection (abscess) yielding Gram-positive cocci in clusters, which is classic for Staphylococcus aureus.
Establishing the organism is required to interpret its expected antimicrobial susceptibility profile.
2
Interpret the clinical failure and culture results.
The infection worsened despite treatment with cephalexin (a first-generation cephalosporin), and cultures demonstrate resistance to oxacillin. This confirms the organism is Methicillin-Resistant Staphylococcus aureus (MRSA).
Oxacillin resistance defines MRSA and implies cross-resistance to all beta-lactam antibiotics, including cephalosporins like cephalexin.
3
Determine the molecular mechanism of resistance for MRSA.
MRSA resistance is mediated by the mecA gene, which is carried on the Staphylococcal cassette chromosome mec (a mobile genetic element).
The mecA gene encodes penicillin-binding protein 2a (PBP2a), a variant peptidoglycan transpeptidase with exceedingly low affinity for beta-lactam antibiotics, allowing the bacteria to synthesize cell walls despite the presence of the drug.

Key Concept

Methicillin-resistant Staphylococcus aureus (MRSA) resists beta-lactam antibiotics (including cephalosporins) via the acquisition of the mecA gene, which encodes an altered penicillin-binding protein (PBP2a) that functions as a variant peptidoglycan transpeptidase with low affinity for beta-lactams.
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Infectious Disease Mechanisms

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