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Access through your institution Buy or subscribe _Nature_ https://doi.org/10.1038/s41586-019-1315-z (2019) The use of whole-cell and biochemical antibiotic screens to identify novel

small-molecule inhibitors to treat _Mycobacterium tuberculosis_ (_Mtb_) infections has been largely unsuccessful because of the inability to comprehensively target a large number of

essential proteins. Johnson et al. developed a drug discovery approach called PROSPECT (primary screening of strains to prioritize expanded chemistry and targets) as an alternative. PROSPECT

involves screening compounds against haploid bacterial genetic mutant strains depleted of 474 essential _Mtb_ genes mainly through conditional proteolysis. Screening pools of 100–150

diverse strains, each containing a unique barcode, against bioactive and unbiased compound libraries generated 8.5 million chemical–genetic interactions to test whether compounds

specifically targeted a particular mutant strain over wild-type strains. This approach identified 40 compounds targeting various processes ranging from DNA gyrase to tryptophan biosynthesis.

In particular, they identified BRD-8000 as an uncompetitive direct inhibitor of the efflux pump EfpA. Overall, the PROSPECT system offers a promising drug discovery approach that enables

identification of compounds that can act on a large range of potential _Mtb_ targets. This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through

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support AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Nature Chemical Biology https://www.nature.com/nchembio/ Grant Miura Authors * Grant Miura View author publications You can also search

for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Grant Miura. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Miura, G.

PROSPECTing for drugs. _Nat Chem Biol_ 15, 759 (2019). https://doi.org/10.1038/s41589-019-0334-2 Download citation * Published: 18 July 2019 * Issue Date: August 2019 * DOI:

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