GSE119158
Transcriptional response of M. tuberculosis to quinazoline-11626252 treatment
We report here lead optimisation efforts of a new series of cytochrome bc1 oxidase inhibitors, the quinazoline derivatives. Four derivatives showed mild to no cytotoxicity as potent in vitro and ex vivo activity in infected THP-1 macrophages against M. tuberculosis. Isolation of resistant mutants to one of the derivatives in M. tuberculosis revealed mutations in both QcrA and QcrB of the cytochrome bc1 oxidase, one of two terminal oxidases of the mycobacterial electron transport chain. Cross-resistance studies, transcriptomic analyses and bioenergetics flux assays provide further evidence of the cytochrome bc1 as the target of the quinazolines compounds. The transcriptomic and bioenergetic profiles obtained when M. tuberculosis was treated with 11626252 are similar to transcriptomic and respiratory signatures of other cytochrome bc1 oxidase inhibitors. Overall design: To gain insight into the initial adaptive response of M. tuberculosis to quinazoline-11626252, the transcriptomes of wild-type H37Rv exposed to quinazoline-11626252 at 10x and 30x MIC for a duration of four hours were examined. Two biological replicates were used for each condition. The control samples (which were part of the same experiment) are available under accession GSM3111057 and GSM3111058.