Structure–Activity Relationships of the MEPicides: <i>N</i>‑Acyl and <i>O</i>‑Linked Analogs of FR900098 as Inhibitors of Dxr from <i>Mycobacterium tuberculosis</i> and <i>Yersinia pestis</i>

Despite continued research efforts, the threat of drug resistance from a variety of bacteria continues to plague clinical communities. Discovery and validation of novel biochemical targets will facilitate development of new drugs to combat these organisms. The methylerythritol phosphate (MEP) pathway to make isoprene units is a biosynthetic pathway essential to many bacteria. We and others have explored inhibitors of the MEP pathway as novel antibacterial agents. <i>Mycobacterium tuberculosis</i>, the causative agent of tuberculosis, and <i>Yersinia pestis</i>, resulting in the plague or “black death”, both rely on the MEP pathway for isoprene production. 1-Deoxy-d-xylulose 5-phosphate reductoisomerase (Dxr) catalyzes the first committed step in the MEP pathway. We examined two series of Dxr inhibitors based on the parent structure of the retrohydroxamate natural product FR900098. The compounds contain either an extended <i>N</i>-acyl or <i>O</i>-linked alkyl/aryl group and are designed to act as bisubstrate inhibitors of the enzyme. While nearly all of the compounds inhibited both Mtb and Yp Dxr to some extent, compounds generally displayed more potent inhibition against the Yp homologue, with the best analogs displaying nanomolar IC<sub>50</sub> values. In bacterial growth inhibition assays, the phosphonic acids generally resulted in poor antibacterial activity, likely a reflection of inadequate permeability. Accordingly, diethyl and dipivaloyloxymethyl (POM) prodrug esters of these compounds were made. While the added lipophilicity did not enhance <i>Yersinia</i> activity, the compounds showed significantly improved antitubercular activities. The most potent compounds have Mtb MIC values of 3–12 μg/mL. Taken together, we have uncovered two series of analogs that potently inhibit Dxr homologues from Mtb and Yp. These inhibitors of the MEP pathway, termed MEPicides, serve as leads for future analog development.