Department of Microbiology and Physiological Systems
Antitubercular Agents; Aspartic Acid Endopeptidases; Bacterial Proteins; Drug Discovery; Drug Evaluation, Preclinical; Drug Resistance, Bacterial; Models, Molecular; Molecular Structure; Mycobacterium tuberculosis; Polyketide Synthases; Sequence Analysis, DNA
Bacteriology | Immunoprophylaxis and Therapy | Pathogenic Microbiology
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.
DOI of Published Version
PLoS One. 2013 Sep 23;8(9):e75245. doi: 10.1371/journal.pone.0075245. eCollection 2013. Link to article on publisher's site
Ioerger TR, O'Malley T, Liao R, Guinn KM, Hickey MJ, Mohaideen N, Murphy KC, Boshoff HI, Mizrahi V, Rubin EJ, Sassetti C, Barry CE, Sherman DR, Parish T, Sacchettini JC. (2013). Identification of new drug targets and resistance mechanisms in Mycobacterium tuberculosis. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1371/journal.pone.0075245. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/574
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