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Abstract
Cholesterol is important for Mycobacterium tuberculosis (Mtb) survival and persistence in the host. We describe a series of 6-azasteroids tested as cholesterol analogs, that are synergistic inhibitors of Mtb viability. The analogs improve Mtb killing efficacy by isoniaizid and bedaquiline, two approved drugs for the treatment of drug-sensitive and drug-resistant Mtb, respectively. In addition, the 6-azasteroids work with existing TB drugs under anaerobic conditions and lower their MICs by greater than 10-fold, suggesting they will work in hypoxic conditions found in infected lungs.
Our work provides strong evidence for an expanded repertoire of cholesterol utilization in Mtb infection that extends beyond the commonly accepted role of cholesterol in nutrition and primary energy generation. We discovered that a stress-resistance regulon (Mce3R) is required for the synergistic activity of 6-azasteroids. Moreover, we demonstrate that cholesterol catabolism is not required for the activity of these inhibitors. Earlier Cirillo, Jacobs and coworkers, established that the mel2 operon residing in the Mce3R regulon is important for persistence and dissemination of Mtb infection in mice (DOI: 10.1128/IAI.01481-08). Thus, an important role of cholesterol utilization for survival of Mtb infection is stress resistance.
Importantly, we demonstrate that this stress-resistance pathway is vulnerable to small molecule targeting.
