A 23-year-old man presents to a clinic within a medical compound in Nigeria. The compound is running a trial looking at whole-genome sequencing of pathogen in suspected infectious disease. He presents following 3-months of feeling hot and sweating at night, and he has recently noticed weight-loss and describes his trousers now slipping down to his hips. His medical history includes HIV which is treated with emtricitabine and tenofovir. He works as a local farmer. Physical examination reveals a thin, somewhat ill-appearing man. A sputum sample is obtained, and Ziehl-Neelsen staining shows acid-fast bacilli. Whole-genome sequencing shows a mutation in the rpoB gene, causing a change in the binding site of RNA polymerase, leading to a change in antibiotic prescription due to a concern of resistance.
To which of the following antibiotics is this pathogen most likely resistant?
- A) Bedaquiline
- B) Ethambutol
- C) Isoniazid
- D) Pyrazinamide
- E) Rifampicin
Rifampicin inhibits RNA by forming a stable complex with RNA-polymerase. rpoB is a known rifampicin resistance gene, with mutations preventing an RNA polymerase-rifampicin complex. Therefore, changes in RNA-polymerase as described here likely prevent rifampicin binding and preventing its effect.
Bedaquiline is a newer anti-tuberculosis drug and inhibits mycobacterial adenosine triphosphate (ATP) synthase. Resistance to bedaquiline is increasing, but the mechanisms of resistance are not yet clearly defined. Changes in RNA polymerase are unlikely to impact bedaquiline function.
Ethambutol works by binding to and inhibiting enzymes that form the cell wall. Changes in the embB gene alter the structure of enzymes that ethambutol binds to. Changes in RNA polymerase are unlikely to impact ethambutol function.
Isoniazid is a bactericidal antibiotic that works by inhibiting TB cell wall formation. KatG is the gene that encodes catalase-peroxidase which activates isoniazid, which is given as a pro-drug. Variants in KatG prevent activation of isoniazid. Changes in RNA polymerase are unlikely to impact isoniazid function.
The mechanism of action of pyrazinamide is unknown. Resistance occurs largely in the pncA gene which encodes the pyrazinamidase (PZase) enzyme. PZase activates pyrazinamide. Changes in RNA polymerase are unlikely to impact pyrazinamide function.
Octavi Casals Farre
Dr. Ted O'Connell