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UDP-3-O-((R)-3-hydroxymyristoyl)-N-glucosamine deacetylase (LpxC) is as an attractive target for the discovery and development of novel antibacterial drugs to address the critical medical need created by multidrug resistant Gram-negative bacteria. By using a scaffold hopping approach on a known family of methylsulfone hydroxamate LpxC inhibitors, several hit series eliciting potent antibacterial activities against Enterobacteriaceae and Pseudomonas aeruginosa were identified. Subsequent hit-to-lead optimization, using cocrystal structures of inhibitors bound to Pseudomonas aeruginosa LpxC as guides, resulted in the discovery of multiple chemical series based on (i) isoindolin-1-ones, (ii) 4,5-dihydro-6H-thieno­[2,3-c]­pyrrol-6-ones, and (iii) 1,2-dihydro-3H-pyrrolo­[1,2-c]­imidazole-3-ones. Synthetic methods, antibacterial activities and relative binding affinities, as well as physicochemical properties that allowed compound prioritization are presented. Finally, in vivo properties of lead molecules which belong to the most promising pyrrolo-imidazolone series, such as 18d, are discussed.

The use of the tellurium-centered Anderson−Evans polyoxotungstate [TeW6O24]6− (TEW) as a crystallization additive has been described. Here, we present the use of TEW as an additive in the crystallization screening of the nucleotide binding domain (NBD) of HSP70. Crystallization screening of the HSP70 NBD in the absence of TEW using a standard commercial screen resulted in a single crystal form. An identical crystallization screen of the HSP70 NBD in the presence of TEW resulted in both the “TEW free” crystal form and an additional crystal form with a different crystal packing. TEW binding was observed in both crystal forms, either as a well-defined molecule or in overlapping alternate positions suggesting translational disorder. The structures were solved by both molecular replacement and single wavelength anomalous diffraction (SAD) using the anomalous signal of a single bound molecule of TEW. This study adds one more example of TEW binding to a protein and influencing its crystallization behavior.

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