Repurposing Avasimibe to Inhibit Bacterial Glycosyltransferases

Area of Science:

• Microbiology
• Pharmacology
• Drug Discovery

Background:

• Bacterial virulence factors are critical targets for novel anti-infective strategies.
• Arginine glycosyltransferases (AGT) are essential enzymes for the virulence of various bacterial pathogens.
• Small molecule inhibitors offer a promising avenue for anti-virulence therapies.

Purpose of the Study:

• To identify and characterize small molecule inhibitors of bacterial virulence factors.
• To evaluate the potential of avasimibe as an anti-virulence agent targeting AGTs.
• To assess the efficacy and safety of avasimibe in vitro and in vivo.

Main Methods:

• High-throughput screening assays to identify potential inhibitors.
• Enzyme activity assays for NleB and SseK AGTs from E. coli and S. enterica.
• Cell-based assays using RAW264.7 macrophage-like cells.
• In vivo studies using a mouse model of Citrobacter rodentium infection.

Main Results:

• Avasimibe inhibited NleB (from C. rodentium and E. coli) and SseK1 (from S. enterica) AGT activity.
• Avasimibe showed no toxicity to mammalian cells and was not bacteriostatic or bactericidal.
• Avasimibe reduced bacterial load in macrophages and significantly improved survival in a mouse infection model.

Conclusions:

• Avasimibe demonstrates potent anti-virulence activity by inhibiting critical bacterial AGTs.
• Avasimibe is a promising candidate for developing novel anti-virulence therapies.
• Further synthetic chemistry efforts on avasimibe derivatives may yield improved anti-bacterial agents.