USMLE PRACTICE QUESTION #122
TOPIC: Infectious Disease + Pharmacology
USMLE practice question #122 will test your pharmacology knowledge about a commonly tested infectious disease.
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A 35-year-old man presents to the clinic with a 3-month history of persistent cough, unintentional weight loss, and night sweats. He emigrated from Southeast Asia 6 months ago. Chest X-ray reveals cavitary lesions in the upper lobes of both lungs. Sputum acid-fast stain is positive for Mycobacterium tuberculosis. Despite adherence to directly observed therapy with isoniazid, rifampin, pyrazinamide, and ethambutol, his symptoms persist after 3 months. Molecular testing identifies a mutation in the rpoB gene of M. tuberculosis. Which of the following best explains the mechanism of resistance associated with this mutation?
A) Efflux pump upregulation preventing intracellular drug accumulation
B) Mutation in the enzyme required for activation of isoniazid
C) Altered binding site for rifampin on bacterial RNA polymerase
D) Impaired conversion of pyrazinamide to its active form in acidic environments
E) Altered permeability of the mycobacterial cell wall to ethambutol
Detailed Breakdown of Answers + Correct Answer Below ⏬
ANSWER + QUESTION BREAKDOWN
It’s important to adopt the correct MENTAL MODEL when answering USMLE questions; it saves time and increases accuracy. The mental model outlined below is a foundational component of our test-taking skills masterclass (check it out if you want to elevate your skills). Here’s how to think through this question:
Step 1. Read the last line to get to the heart of the question: “Which of the following best explains the mechanism of resistance associated with this mutation?”
Step 2: Is this a first-, second-, or third-order question?
Answer: 1st order. 1st: Correctly identify the mechanism of resistance.
Step 3: Read the vignette carefully and ask yourself: “Based on the given mutation, the most likely cause of resistance is __________________”
Step 4. Look at the answer choices and select the option most closely resembling your final thought from “Step 3” above.
GENERAL ANALYSIS
Molecular testing reveals a mutation in the rpoB gene, which is strongly associated with rifampin resistance.
Rifampin resistance in M. tuberculosis is primarily caused by mutations in the rifampin resistance-determining region (RRDR) of the rpoB gene, which encodes the β-subunit of bacterial RNA polymerase. These mutations alter the binding site of rifampin on RNA polymerase, reducing its affinity for the drug and rendering it ineffective.
ANSWER CHOICES:
CHOICE A: Efflux pump upregulation preventing intracellular drug accumulation
Explanation: Efflux pumps can contribute to drug resistance by actively exporting antibiotics out of bacterial cells. This mechanism is seen in some bacterial species and can confer low-level resistance to multiple drugs.
Rifampin resistance in M. tuberculosis is primarily due to mutations in the rpoB gene that alter the drug's binding site, not efflux pump activity.
CHOICE B: Mutation in the enzyme required for activation of isoniazid
Explanation: Isoniazid requires activation by the bacterial enzyme KatG to exert its bactericidal effect. Mutations in the katG gene can lead to isoniazid resistance.
This mechanism explains isoniazid resistance but does not account for rifampin resistance caused by rpoB mutations.
CHOICE C: Altered binding site for rifampin on bacterial RNA polymerase
Explanation: Rifampin inhibits bacterial transcription by binding to the β-subunit of RNA polymerase (encoded by the rpoB gene). Mutations in the RRDR of rpoB alter the structure of this binding site, reducing rifampin's affinity for RNA polymerase and conferring resistance.
The mutation identified in this patient’s rpoB gene directly alters rifampin’s target site, making this the most likely mechanism of resistance.
CHOICE D: Impaired conversion of pyrazinamide to its active form in acidic environments
Explanation: Pyrazinamide requires conversion to its active form (pyrazinoic acid) by the bacterial enzyme pncA. Mutations in the pncA gene can lead to pyrazinamide resistance.
This mechanism explains pyrazinamide resistance but does not account for rifampin resistance due to rpoB mutations.
CHOICE E: Altered permeability of the mycobacterial cell wall to ethambutol
Explanation: Ethambutol inhibits arabinosyltransferase enzymes involved in mycobacterial cell wall synthesis. Resistance can occur through mutations that reduce drug permeability or alter target enzymes.
This mechanism explains ethambutol resistance but does not account for rifampin resistance caused by rpoB mutations.
FINAL VERDICT…
CORRECT ANSWER: C) Altered binding site for rifampin on bacterial RNA polymerase
Mutations in the rpoB gene, particularly within its RRDR, alter rifampin’s binding site on RNA polymerase. This structural change reduces rifampin’s ability to inhibit transcription and leads to drug resistance. These mutations are responsible for more than 90% of rifampin-resistant TB cases and are a hallmark of multidrug-resistant TB (MDR-TB).
By identifying an altered binding site on RNA polymerase due to an rpoB mutation, molecular testing confirms rifampin resistance and provides critical information for tailoring treatment strategies in this patient with persistent TB symptoms.
KEY CONCEPTS:
Rifampin Mechanism of Action:
Rifampin binds to the β-subunit of bacterial RNA polymerase (encoded by rpoB) and inhibits transcription.
This action is bactericidal against M. tuberculosis.
Mechanism of Rifampin Resistance:
Mutations in the RRDR of rpoB, particularly at codons 426–452, alter rifampin’s binding site on RNA polymerase.
These mutations reduce drug-binding affinity and confer high-level resistance.
Clinical Implications:
Rifampin resistance often indicates multidrug-resistant TB (MDR-TB), as it frequently co-occurs with isoniazid resistance.
Molecular testing for rpoB mutations is critical for diagnosing rifampin-resistant TB and guiding treatment adjustments.
Differential Mechanisms of Resistance for Other Drugs:
Isoniazid: Mutations in katG or inhA genes.
Pyrazinamide: Mutations in pncA impair activation.
Ethambutol: Mutations affecting arabinosyltransferases or cell wall permeability.
Management of Rifampin-Resistant TB:
Requires second-line drugs such as fluoroquinolones (e.g., moxifloxacin) or injectable agents (e.g., amikacin) as part of a multidrug regimen.
Directly observed therapy (DOT) remains essential for ensuring adherence and preventing further resistance development.
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