PROSPECTing for drugs | Nature Chemical Biology

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.

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