New 2-Thiopyridines as Potential Candidates for Killing both Actively Growing and Dormant Mycobacterium tuberculosis Cells

Abstract

ABSTRACTFromin vivoobservations, a majority ofM. tuberculosiscells in latently infected individuals are in a dormant and probably nonculturable state, display little metabolic activity, and are phenotypically resistant to antibiotics. Despite many attempts, no specific antimicrobials effective against latent tuberculosis have yet been found, partly because of a lack of reliable and adequatein vitromodels for screening of drug candidates. We propose here a novelin vitromodel ofM. tuberculosisdormancy that meets the important criteria of latency, namely, nonculturability of cells, considerable reduction of metabolic activity, and significant phenotypic resistance to the first-line antibiotics rifampin and isoniazid. Using this model, we found a new group of 2-thiopyridine derivatives that had potent antibacterial activity against both actively growing and dormantM. tuberculosiscells. By means of the model ofM. tuberculosisnonculturability, several new 2-thiopyridine derivatives were found to have potent antitubercular activity. The compounds are effective against both active and dormantM. tuberculosiscells. The bactericidal effects of compounds against dormantM. tuberculosiswas confirmed by using three differentin vitromodels of tuberculosis dormancy. The model of nonculturability could be used as a reliable tool for screening drug candidates, and 2-thiopyridine derivatives may be regarded as prominent compounds for further development of new drugs for curing latentM. tuberculosisinfection.