A Coumarin-Based Analogue of Thiacetazone as Dual Covalent Inhibitor and Potential Fluorescent Label of HadA in <i>Mycobacterium tuberculosis</i>
Asma Farjallah, Laurent R. Chiarelli, Martin Forbak, Giulia Degiacomi, Mathieu Danel, Fernanda Goncalves, Chantal Carayon, Cendrine Seguin, Marco Fumagalli, Monika Záhorszká, Elodie Vega, Souhir Abid, Anna E. Grzegorzewicz, Mary Jackson, António Peixoto, Jana Korduláková, Maria Rosalia Pasca, Christian Lherbet, Stefan Chassaing
Abstract
A novel coumarin-based molecule, designed as a fluorescent surrogate of a thiacetazone-derived antitubercular agent, was quickly and easily synthesized from readily available starting materials. This small molecule, coined Coum-TAC, exhibited a combination of appropriate physicochemical and biological properties, including resistance toward hydrolysis and excellent antitubercular efficiency similar to that of well-known thiacetazone derivatives, as well as efficient covalent labeling of HadA, a relevant therapeutic target to combat Mycobacterium tuberculosis. More remarkably, Coum-TAC was successfully implemented as an imaging probe that is capable of labeling Mycobacterium tuberculosis in a selective manner, with an enrichment at the level of the poles, thus giving for the first time relevant insights about the polar localization of HadA in the mycobacteria.