Identification of new drug targets and resistance mechanisms in Mycobacterium tuberculosis.
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abstract
Identification of new drug targets is vital for the advancement of drug discovery against Mycobacterium tuberculosis, especially given the increase of resistance worldwide to first- and second-line drugs. Because traditional target-based screening has largely proven unsuccessful for antibiotic discovery, we have developed a scalable platform for target identification in M. tuberculosis that is based on whole-cell screening, coupled with whole-genome sequencing of resistant mutants and recombineering to confirm. The method yields targets paired with whole-cell active compounds, which can serve as novel scaffolds for drug development, molecular tools for validation, and/or as ligands for co-crystallization. It may also reveal other information about mechanisms of action, such as activation or efflux. Using this method, we identified resistance-linked genes for eight compounds with anti-tubercular activity. Four of the genes have previously been shown to be essential: AspS, aspartyl-tRNA synthetase, Pks13, a polyketide synthase involved in mycolic acid biosynthesis, MmpL3, a membrane transporter, and EccB3, a component of the ESX-3 type VII secretion system. AspS and Pks13 represent novel targets in protein translation and cell-wall biosynthesis. Both MmpL3 and EccB3 are involved in membrane transport. Pks13, AspS, and EccB3 represent novel candidates not targeted by existing TB drugs, and the availability of whole-cell active inhibitors greatly increases their potential for drug discovery.
Ioerger, T. R., O'Malley, T., Liao, R., Guinn, K. M., Hickey, M. J., Mohaideen, N., ... Sacchettini, J. C.
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Ioerger, Thomas R||O'Malley, Theresa||Liao, Reiling||Guinn, Kristine M||Hickey, Mark J||Mohaideen, Nilofar||Murphy, Kenan C||Boshoff, Helena IM||Mizrahi, Valerie||Rubin, Eric J||Sassetti, Christopher M||Barry, Clifton E||Sherman, David R||Parish, Tanya||Sacchettini, James C
