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

Area of Science:

• Medicinal Chemistry
• Microbiology
• Drug Discovery

Background:

• Antimicrobial resistance (AMR) is a critical global health threat, demanding new drugs with novel mechanisms.
• Fosmidomycin inhibits the non-mevalonate pathway enzyme IspC but has poor pharmacokinetics.
• Boron-containing compounds offer potential as isosteres for drug design.

Purpose of the Study:

• To synthesize and evaluate boron-containing analogs of fosmidomycin as IspC inhibitors.
• To explore the antimicrobial potential of these novel boron compounds.
• To investigate alternative mechanisms of action for active compounds.

Main Methods:

• Synthesis of 15 boron-containing fosmidomycin analogs.
• In vitro evaluation of IspC inhibition.
• Antimicrobial susceptibility testing against pathogenic bacteria.
• Mechanistic studies to elucidate modes of action.

Main Results:

• Boron analogs did not show significant IspC inhibition, indicating limited utility as phosphonate isosteres in this context.
• Several benzoxaborole derivatives exhibited potent antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA) and other pathogens.
• Mechanistic investigations revealed that active compounds target pathways distinct from MEP pathway inhibition.

Conclusions:

• Boron moieties may not be suitable phosphonate isosteres for IspC inhibition.
• Benzoxaboroles represent a promising class of novel boron-containing antimicrobials.
• These findings support the development of next-generation boron-based drugs against resistant infections.