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Difficulty: MediumInfectious Disease Mechanisms

A 42-year-old recent immigrant from Southeast Asia presents to the outpatient clinic with a 6-week history of low-grade fever, drenching night sweats, chronic cough with blood-tinged sputum, and a 5-kg (11-lb) unintentional weight loss. A chest radiograph demonstrates a cavitary lesion in the right upper lobe. Sputum smear is positive for acid-fast bacilli. The patient is initiated on standard quadruple antimicrobial therapy. Several weeks later, the state health department reports that the isolated organism is resistant to the agent within the regimen that primarily inhibits mycolic acid synthesis. Which of the following is the most likely molecular mechanism responsible for this specific drug resistance?

  1. A
    Structural alteration of the DNA-dependent RNA polymerase
  2. B
    Covalent modification of the drug by a bacterial acetyltransferase
  3. Decreased activity of a bacterial catalase-peroxidaseAnswer
  4. D
    Overexpression of a membrane-associated arabinosyltransferase
  5. E
    Increased activity of a transmembrane drug efflux pump

Answer

Decreased activity of a bacterial catalase-peroxidase
The patient is infected with Mycobacterium tuberculosis and is experiencing resistance to the agent in the standard regimen that inhibits mycolic acid synthesis, which is isoniazid. Isoniazid is a prodrug that must enter the bacterial cell and be activated by the mycobacterial enzyme catalase-peroxidase, which is encoded by the katG gene. Once activated, it binds to NAD+ or NADP+ to form adducts that inhibit InhA, a reductase essential for mycolic acid synthesis. The most frequent and clinically significant mechanism of resistance to isoniazid is a mutation in the katG gene that decreases or eliminates catalase-peroxidase activity, preventing the prodrug from being converted into its active form.

Step-by-Step Solution

1
Identify the infectious disease process and the specific antimicrobial agent in question.
The clinical presentation (cavitary apical lung lesion, acid-fast bacilli, systemic symptoms) indicates active pulmonary tuberculosis. The antimicrobial agent in the standard quadruple therapy (RIPE) that specifically inhibits mycolic acid synthesis is isoniazid.
Accurately identifying the target drug is required before determining its mechanism of resistance.
2
Determine the molecular mechanism of resistance for the identified agent.
Isoniazid is a prodrug that requires activation by the mycobacterial catalase-peroxidase enzyme, KatG. The most common mechanism of isoniazid resistance is a mutation in the katG gene resulting in decreased or absent enzyme activity.
Without active KatG, isoniazid cannot be converted into its active radical form, thereby conferring resistance.

Key Concept

The primary mechanism of isoniazid resistance in Mycobacterium tuberculosis is the decreased activity or loss of the bacterial KatG (catalase-peroxidase) enzyme, which is necessary to activate the prodrug.
Estimated Time:1m 0s
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Topics

Infectious Disease Mechanisms

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