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Difficulty: EasyInfectious Disease Mechanisms

A 72-year-old retired teacher residing in an assisted living community is evaluated at the hospital for a 3-day history of chills, rust-colored sputum, and shortness of breath. Temperature is 38.9°C (102°F), blood pressure is 110/65 mmHg, and oxygen saturation is 91% on room air. Auscultation reveals bronchial breath sounds and crackles over the left lower lung fields. A sputum Gram stain demonstrates numerous neutrophils and lancet-shaped, Gram-positive diplococci. Empiric therapy is initiated, but susceptibility testing later indicates the isolated organism requires a high minimum inhibitory concentration (MIC) to penicillin G and ceftriaxone. Which of the following best describes the underlying molecular mechanism responsible for this pathogen's resistance profile?

  1. Structural modification of native transpeptidases resulting in decreased drug affinityAnswer
  2. B
    Secretion of plasmid-mediated enzymes that cleave the beta-lactam ring
  3. C
    Upregulation of transmembrane efflux pumps that actively expel the drug
  4. D
    Target-site alteration via methylation of the 50S ribosomal subunit
  5. E
    Decreased cellular permeability due to structural changes in outer membrane porins

Answer

Structural modification of native transpeptidases resulting in decreased drug affinity
The patient is infected with Streptococcus pneumoniae, as indicated by the classic presentation of lobar pneumonia with rust-colored sputum and a sputum Gram stain showing lancet-shaped, Gram-positive diplococci. Penicillins and cephalosporins exert their bactericidal effect by binding to and inhibiting penicillin-binding proteins (PBPs), which are transpeptidases essential for bacterial cell wall peptidoglycan cross-linking. S. pneumoniae develops resistance to these beta-lactam antibiotics via the acquisition of mosaic PBP genes (primarily PBP 1a, 2b, and 2x) through natural transformation and homologous recombination. This genetic change results in the production of structurally modified transpeptidases that possess significantly decreased affinity for the drugs. Consequently, cell wall synthesis can continue even in the presence of the antibiotic.

Step-by-Step Solution

1
Identify the infecting pathogen from the clinical presentation and laboratory findings.
The pathogen is Streptococcus pneumoniae.
The patient has community-acquired pneumonia with rust-colored sputum, and the Gram stain shows lancet-shaped, Gram-positive diplococci, which is the classic description of S. pneumoniae.
2
Determine the molecular mechanism of resistance to penicillins and cephalosporins for this specific organism.
Alteration of penicillin-binding proteins (PBPs).
Unlike many other bacteria, S. pneumoniae does not produce beta-lactamases. Instead, it acquires mosaic genes via natural transformation that alter the structure of its PBPs (transpeptidases), reducing their affinity for beta-lactam antibiotics.

Key Concept

Mechanism of beta-lactam resistance in Streptococcus pneumoniae
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Topics

Infectious Disease Mechanisms

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