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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
Identification of New Drug Targets and Resistance Mechanisms in Mycobacterium tuberculosis
PLoS ONE, Volume 8, No. 9, Article e75245, Year 2013
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Description
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. © 2013 Ioerger et al.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC3781026/bin/pone.0075245.s001.doc
Authors & Co-Authors
Ioerger, Thomas Richard
Unknown Affiliation
O'Malley, Theresa
Unknown Affiliation
Liao, Reiling P.
Unknown Affiliation
Guinn, Kristine M.
Unknown Affiliation
Hickey, Mark J.
Unknown Affiliation
Mohaideen, Nilofar
Unknown Affiliation
Murphy, Kenan C.
Unknown Affiliation
Boshoff, Helena Ingrid M.
Unknown Affiliation
Mizrahi, Valerie
Unknown Affiliation
Rubin, Eric Joseph
Unknown Affiliation
Sassetti, Christopher M.
Unknown Affiliation
Barry, Clifton Earl
Unknown Affiliation
Sherman, David R.
Unknown Affiliation
Parish, Tanya
Unknown Affiliation
Sacchettini, James C.
Unknown Affiliation
Statistics
Citations: 206
Authors: 15
Affiliations: 9
Identifiers
Doi:
10.1371/journal.pone.0075245
e-ISSN:
19326203
Research Areas
Infectious Diseases