Further Insight into Crystal Structures of Escherichia coli IspH/LytB in Complex with Two Potent Inhibitors of the MEP Pathway: A Starting Point for Rational Design of New Antimicrobials

IspH, also called LytB, a protein involved in the biosynthesis of isoprenoids via the methylerythritol phosphate pathway, is an attractive target for the development of new antimicrobial drugs. Here, we report crystal structures of Escherichia coli IspH in complex with the two most potent inhibitors known to date, (E)-4-mercapto-3-methylbut-2-en-1-yl diphosphate (TMBPP) and (E)-4-amino-3-methylbut-2-en-1-yl diphosphate (AMBPP) at 1.95 A and 1.7 A resolution, respectively. The structure of the E.coli IspH:TMBPP complex exhibited two conformers of the inhibitor. This unexpected feature has been exploited to design and evolve in silico new antimicrobial candidates.