Metabolically stable tricyclic spirolactam inhibitors of M. tuberculosis Ndh-2 show in vivo efficacy and validate the target in mice
- SAR and structure-property work on tricyclic spirolactam (TriSLa) Ndh inhibitors addressed the metabolic instability of earlier analogs and yielded BDM91465.
- Cryo-EM placed the compound in the menaquinone pocket of Ndh, consistent with the SAR.
- It showed favorable pharmacokinetics, with exposure sustained above its MIC.
- In mice it lowered bacterial burden, mirroring genetic Ndh-2 inactivation and supporting Ndh-2 as a druggable target.
💡 Points Based on the abstract
Fixing metabolic liability while keeping the quinone-pocket fit is the hard part with Ndh-2 inhibitors; earlier phenothiazine-type binders were never drug-like enough to test the target. Mouse efficacy mirroring genetic inactivation is a strong validation. I'd ask about resistance frequency, activity against drug-resistant strains, and combination behavior in a regimen, since TB is never monotherapy.