Repurposing libraries of eukaryotic protein kinase inhibitors for antibiotic discovery

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Abstract
With the rise in resistance that inevitably follows the clinical deployment of an antibiotic, there is a continual need for new antibiotic discovery, development and approval. Food and Drug Administration approvals for Synercid (quinupristin/dalfopristin) in 1999, Zyvox (linezolid) in 2000, and Cubicin (daptomycin) in 2003 have addressed life-threatening infections from drug-resistant Gram-positive bacteria such as Staphylococcus aureus, Streptococcus pneumomiae, and Enterococcus faecalis. However, because these antibiotics are not active against an emerging class of nosocomial pathogens (multidrug-resistant Gram-negative bacteria, including strains of Klebsiella, Acinetobacter and Pseudomonas) there is renewed focus on developing treatments for infections caused by Gram-negative bacteria. To this end, in this issue of PNAS Miller et al. (1) report a novel approach to discovering new classes of antibiotics. Although bacterial genome sequencing and genetics have identified essential genes as potential targets for new antibiotics, efforts to screen synthetic chemical libraries have been disappointingly unproductive (2). One possible explanation for the low yield is the bias, historical and contemporary, of pharmaceutical companies' synthetic small molecule libraries for eukaryotic rather than prokaryotic targets. Miller et al. (1) sought to turn this paradigm on its head by making a virtue of the depth of such a library, in this case composed of protein kinase inhibitors. Even though protein kinases are much less widespread in bacterial metabolism, Miller et al. set out to determine whether their library contained ATP analogs that could kill bacterial cells potently and selectively. The Pfizer team (1) made use of the company's screening file, comprising some 1.6 million compounds. …