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To the Editor: The established anti-tuberculosis agents isoniazid and ethionamide are pro-drugs with distinct activation pathways and a common target. Isoniazid is bactericidal and considered essential despite increasing resistance rates and acetylator-genotype dependent elimination. Ethionamide, owing to dose-dependent gastrointestinal intolerability, is recommended only for extensive drug resistance and tuberculosis meningitis (1). In 2017, the Journal heralded the potential revival of ethionamide (2, 3). Cryptic, secondary bacterial systems for ethionamide bioactivation might enhance its potency without increasing toxicity (4). Alpibectir (BVL-GSK098), a first-in-class small molecule targeting a mycobacterial transcription regulator, was predicted to reduce the clinical dose by at least two thirds from ≥750mg to ≤250mg (4). This could decrease ethionamide intolerability and resistance and, with a few exceptions, isoniazid resistance (5). We prospectively randomized 105 newly diagnosed adults with rifampicin-susceptible pulmonary tuberculosis to groups of 14 to 16 participants receiving seven days of once daily isoniazid 300mg, ethionamide 250mg or 750mg, or alpibectir/ethionamide 9/250mg, 27/125mg, 27/250mg or 27/500mg (NCT05473195). Participants in Cape Town, South Africa, were hospitalised and monitored daily for adverse events (full details in the study protocol at nejm.org). Sputum collected overnight was assessed for the change in colony forming units (see Supplementary Appendix). This work was IRB approved and all participants provided written informed consent.

e Town, South Africa, were hospitalised and monitored daily for adverse events (full details in the study protocol at nejm.org). Sputum collected overnight was assessed for the change in colony forming units (see Supplementary Appendix). This work was IRB approved and all participants provided written informed consent. Ethionamide 750mg demonstrated activity similar to that of isoniazid (Figure 1). Ethionamide activity was dose-related and became more potent with increasing alpibectir doses. Investigator assessed drug-related adverse reactions were mostly mild or moderate gastrointestinal events that increased in frequency with higher ethionamide doses (Supplementary Appendix). Proof of concept was established with 27mg alpibectir that potentiated the activity of 250mg ethionamide to a level similar to both 750mg ethionamide and 300mg isoniazid while maintaining tolerability. An ongoing 14-day trial with alpibectir/ethionamide 45/125mg and 45/250mg will assist to select the optimal dose combination (NCT05473195). Longer clinical trials will evaluate an alpibectir/ethionamide fixed dose combination as part of novel regimens or as replacement for isoniazid in first-line treatment where isoniazid resistance is common. Sixty years after its introduction, ethionamide may yet find its place.