Large-scale chemical–genetics yields new M. tuberculosis inhibitor classes
| Autor: | Dirk Schnappinger, Rebecca E Audette, Kristine M. Guinn, Michael Fitzgerald, Michelle Gardner, Carolina Trujillo, Joshua Davis, Joshua B. Wallach, Jessica T. Pinkham, Deborah T. Hung, Nirmalya Bandyopadhyay, Mary Stanley, Natalia Betancourt, Christina Gallo, Megan K. Proulx, Jennifer A McConnell, Christopher M. Sassetti, Sofia Kennedy, Elisabeth Meyer, James Gomez, Kayla Delano, Paula A Pino, Emily LaVerriere, K. G. Papavinasasundaram, Eric S. Lander, Eric J. Rubin, Michael H Serrano-Wu, Emma Office, Caitlin E Moss, Naomi Song, Nadine Ruecker, Thomas R. Ioerger, Israel Da Silva, Matthew Thompson, Christopher Watson, Sabine Ehrt, Shoko Wakabayashi, Brian K. Hubbard, Tomohiko Kawate, Kenan C. Murphy, Rebecca Korn, Raymond M. Nietupski, Eachan O. D. Johnson, Aaron Golas |
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| Rok vydání: | 2019 |
| Předmět: |
medicine.drug_class
Antibiotics Antitubercular Agents Microbial Sensitivity Tests Drug resistance Computational biology DNA gyrase Substrate Specificity Small Molecule Libraries Mycobacterium tuberculosis 03 medical and health sciences chemistry.chemical_compound Folic Acid RNA polymerase Drug Discovery medicine Topoisomerase II Inhibitors Tuberculosis Molecular Targeted Therapy Gene 030304 developmental biology 0303 health sciences Multidisciplinary biology 030306 microbiology Drug discovery Tryptophan Reproducibility of Results Drug Resistance Microbial biology.organism_classification Mycolic Acids chemistry DNA Gyrase Chemical genetics Gene Deletion |
| Zdroj: | Nature. 571:72-78 |
| ISSN: | 1476-4687 0028-0836 |
| DOI: | 10.1038/s41586-019-1315-z |
| Popis: | New antibiotics are needed to combat rising levels of resistance, with new Mycobacterium tuberculosis (Mtb) drugs having the highest priority. However, conventional whole-cell and biochemical antibiotic screens have failed. Here we develop a strategy termed PROSPECT (primary screening of strains to prioritize expanded chemistry and targets), in which we screen compounds against pools of strains depleted of essential bacterial targets. We engineered strains that target 474 essential Mtb genes and screened pools of 100–150 strains against activity-enriched and unbiased compound libraries, probing more than 8.5 million chemical–genetic interactions. Primary screens identified over tenfold more hits than screening wild-type Mtb alone, with chemical–genetic interactions providing immediate, direct target insights. We identified over 40 compounds that target DNA gyrase, the cell wall, tryptophan, folate biosynthesis and RNA polymerase, as well as inhibitors that target EfpA. Chemical optimization yielded EfpA inhibitors with potent wild-type activity, thus demonstrating the ability of PROSPECT to yield inhibitors against targets that would have eluded conventional drug discovery. A high-throughput chemical–genetic screening approach for the discovery of targets and chemicals to treat Mycobacterium tuberculosis yields tenfold more hit compounds than conventional whole-cell screening methods. |
| Databáze: | OpenAIRE |
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