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

## TL;DR

This study explores boron-based compounds as alternatives to fosmidomycin, finding that while they don't target the intended enzyme, some show strong antimicrobial activity against drug-resistant pathogens.

## Contribution

The discovery of benzoxaborole compounds with antimicrobial activity against resistant pathogens through alternative mechanisms.

## Key findings

- Boron-containing analogs of fosmidomycin did not inhibit IspC effectively.
- Benzoxaborole compounds showed significant activity against MRSA, E. coli, and C. albicans.
- Mechanistic studies confirmed these compounds act through pathways other than MEP inhibition.

## Abstract

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 Staphylococcus aureus (MRSA), E. coli, and C. albicans. 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.