Expanding\nthe Chemical Space of Reverse Fosmidomycin\nAnalogs

Multidrug-resistant pathogens pose a major threat to\nhuman health,\nnecessitating the identification of new drug targets and lead compounds\nthat are not susceptible to cross-resistance. This study demonstrates\nthat novel reverse thia analogs of the phosphonohydroxamic acid antibiotic\nfosmidomycin inhibit 1-deoxy-d-xylulose 5-phosphate reductoisomerase\n(DXR), an essential enzyme for Plasmodium falciparum, Escherichia coli, and Mycobacterium tuberculosis that is absent in humans.\nSome novel analogs with large α-phenyl substituents exhibited\nstrong inhibition across these three DXR orthologues, surpassing the\ninhibitory activity of fosmidomycin. Despite nanomolar target inhibition,\nthe new DXR inhibitors demonstrated mainly weak or no <i>in vitro</i> growth inhibition of the pathogens. Crystallographic studies revealed\nthat compounds <b>12a</b> and <b>12b</b> induce an open <i>Pf</i>DXR conformation and that the enzyme selectively binds\nthe <i>S</i>-enantiomers. The study underscores the difficulties\nof achieving potent cellular activity despite strong DXR inhibition\nand emphasizes the need for novel structural optimization strategies\nand comprehensive pharmacokinetic studies.