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Difficulty: MediumInfectious Disease Mechanisms

A 47-year-old woman is evaluated in the emergency department for worsening shortness of breath, productive cough, and fever. She was diagnosed with community-acquired pneumonia at an urgent care clinic four days ago. Due to a documented history of severe anaphylaxis to amoxicillin, she was prescribed oral azithromycin. Despite adherence to the medication regimen, her symptoms have progressed. Vital signs show a temperature of 39.1°C (102.4°F), heart rate of 112/min, blood pressure of 110/65 mm Hg, and respiratory rate of 24/min. A chest radiograph reveals a dense right lower lobe consolidation. Initial blood cultures return positive for Streptococcus pneumoniae. Antimicrobial susceptibility testing indicates that the isolate is highly resistant to both azithromycin and clindamycin, but susceptible to levofloxacin and vancomycin. Which of the following molecular modifications is most likely responsible for this pathogen's specific resistance profile?

  1. Post-transcriptional methylation of an adenine residue in the 23S ribosomal RNAAnswer
  2. B
    ATP-dependent transport of the therapeutic agent out of the intracellular space
  3. C
    Recombination events leading to decreased affinity of cell wall synthesizing enzymes
  4. D
    Acquisition of a plasmid encoding a drug-inactivating acetyltransferase
  5. E
    Amino acid substitutions within the catalytic domain of topoisomerase IV

Answer

The correct cellular mechanism is the post-transcriptional methylation of an adenine residue in the 23S ribosomal RNA.
The patient's Streptococcus pneumoniae isolate demonstrates resistance to both azithromycin (a macrolide) and clindamycin (a lincosamide). These two drug classes, along with streptogramin B, share overlapping binding sites on the 50S bacterial ribosomal subunit. The expression of the erm (erythromycin ribosome methylation) gene produces an enzyme that methylates a specific adenine residue on the 23S rRNA of the 50S subunit. This target-site structural modification sterically hinders the binding of all three drug classes, resulting in the MLS_B resistance phenotype. Because the isolate in the vignette is resistant to both drug classes, ribosomal methylation is the definitive mechanism.

Step-by-Step Solution

1
Analyze the susceptibility report.
The Streptococcus pneumoniae isolate is resistant to a macrolide (azithromycin) and a lincosamide (clindamycin).
Identifying the exact pattern of cross-resistance is required to deduce the underlying molecular mechanism.
2
Correlate the resistance pattern with known bacterial phenotypes.
Combined resistance to macrolides and lincosamides represents the MLS_B (Macrolide, Lincosamide, Streptogramin B) resistance phenotype.
Different resistance genes produce distinct phenotypic profiles. The mef gene produces isolated macrolide resistance, while the erm gene produces the broader MLS_B phenotype.
3
Identify the molecular function of the associated gene.
The erm gene encodes an enzyme that methylates the 23S rRNA component of the 50S ribosomal subunit.
Methylation structurally alters the shared binding site of both macrolides and lincosamides, rendering both drug classes ineffective.

Key Concept

Macrolide resistance in Streptococcus pneumoniae can occur via target-site methylation (erm gene, conferring cross-resistance to clindamycin) or active efflux (mef gene, retaining susceptibility to clindamycin).
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Topics

Infectious Disease Mechanisms

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