Publication: Large-Scale Chemical–genetics Yields New M. Tuberculosis Inhibitor Classes
No Thumbnail Available
Open/View Files
Date
2019-06-19
Published Version
Journal Title
Journal ISSN
Volume Title
Publisher
Springer Science and Business Media LLC
The Harvard community has made this article openly available. Please share how this access benefits you.
Citation
Johnson, Eachan O, Emily LaVerriere, Emma Office, Mary Stanley, Elisabeth Meyer, Tomohiko Kawate, James E Gomez, Rebecca E Audette, Nirmalya Bandyopadhyay, Natalia Betancourt, Kayla Delano, Israel Da Silva, Joshua Davis, Christina Gallo, Michelle Gardner, Aaron J Golas, Kristine M. Guinn, Sofia Kennedy, Rebecca Korn, Jennifer A McConnell, Caitlin E. Moss, Kenan C Murphy, Raymond M. Nietupski, Kadamba G. Papavinasasundaram, Jessica T. Pinkham, Paula A. Pino, Megan K Proulx, Nadine Ruecker, Naomi Song, Matthew Thompson, Carolina Trujillo, Shoko Wakabayashi, Joshua B Wallach, Christopher Watson, Thomas R. Ioerger, Eric S. Lander, Brian K. Hubbard, Michael H. Serrano-Wu, Sabine Ehrt, Michael Fitzgerald, Eric J. Rubin, Christopher M. Sassetti, Dirk Schnappinger, and Deborah T. Hung. 2019. Large-scale Chemical-genetics Yields New M. Tuberculosis Inhibitor Classes. Nature 571, no. 7763: 72-78.
Research Data
Abstract
New antibiotics are needed to combat rising resistance, with new Mycobacterium tuberculosis (Mtb) drugs of highest priority. Conventional whole-cell and biochemical antibiotic screens have failed. We developed a novel strategy termed PROSPECT (PRimary screening Of Strains to Prioritize Expanded Chemistry and Targets) in which we screen compounds against pools of strains depleted for essential bacterial targets. We engineered strains targeting 474 Mtb essential genes and screened pools of 100-150 strains against activity-enriched and unbiased compounds libraries, probing >8.5-million chemical-genetic interactions. Primary screens identified >10-fold more hits than screening wild-type Mtb alone, with chemical-genetic interactions providing immediate, direct target insight. We identified >40 novel compounds targeting DNA gyrase, cell wall, tryptophan, folate biosynthesis, and RNA polymerase, as well as inhibitors of a novel target EfpA. Chemical optimization yielded EfpA inhibitors with potent wild-type activity, thus demonstrating PROSPECT’s ability to yield inhibitors against novel targets which would have eluded conventional drug discovery.
Description
Other Available Sources
Keywords
Antitubercular Agents–Classification, DNA Gyrase–Isolation & Purification, Drug Discovery–Pharmacology, Drug Resistance, Microbial–Metabolism, Folic Acid–Methods, Gene Deletion–Biosynthesis, Microbial Sensitivity Tests–Methods, Molecular Targeted Therapy–Cytology, Mycobacterium Tuberculosis–Drug Effects, Mycolic Acids–Enzymology, Reproducibility of Results–Genetics, Small Molecule Libraries–Metabolism, Substrate Specificity–Classification, Topoisomerase II Inhibitors–Isolation & Purification, Tryptophan–Pharmacology, Tuberculosis–Isolation & Purification, Tuberculosis
Terms of Use
This article is made available under the terms and conditions applicable to Other Posted Material (LAA), as set forth at Terms of Service