Boron-Containing Analogs of Fosmidomycin: Benzoxaborole Derivatives Exhibit Promising Activity Against Resistant Pathogens

The rise of antimicrobial resistance presents an urgent challenge that necessitates the development of novel therapeutic agents with distinct mechanisms of action. This research explores boron-containing compounds as potential neutral phosphate/phosphonate isosteres of fosmidomycin, a potent inhibitor of 1-deoxy-d-xylulose-5-phosphate reductoisomerase (IspC) within the nonmevalonate isoprenoid biosynthesis (MEP) pathway, with limited clinical utility due to poor pharmacokinetics. We report the synthesis of a library of 15 boron-containing analogs of fosmidomycin and their comprehensive evaluation as IspC inhibitors and antimicrobial agents. The compounds did not demonstrate significant activity against the intended IspC target, thus providing evidence that these boron moieties may have limited utility as phosphonate isosteres in this system. However, our investigation yielded unexpected and valuable antimicrobial discoveries. Several benzoxaborole compounds demonstrated significant activity against pathogenic microbes, including methicillin-resistant <i>Staphylococcus aureus</i> (MRSA), <i>E. coli</i>, and <i>C. albicans</i>. Mechanistic studies confirmed that these compounds operate through alternative pathways distinct from MEP pathway inhibition. These results provide a foundation for the rational design of next-generation boron-containing antimicrobials with enhanced potency and selectivity against resistant pathogens, including MRSA.