Translation of Microbiota Short-Chain Fatty Acid Mechanisms Affords Anti-infective Acyl-Salicylic Acid Derivatives

The discovery of specific microbiota
metabolite mechanisms has
begun to motivate new therapeutic approaches. Inspired by our mechanistic
studies of microbiota-derived short chain fatty acid (SCFA) acylation
of bacterial virulence factors, here we explored covalent protein
acylation therapeutics as potential anti-infectives. For these studies,
we focused on acetyl-salicylic acid, aspirin, and discovered that
SCFA analogues such as butyryl-salicylic acid showed significantly
improved anti-infective activity against Salmonella Typhimurium. Structure–activity studies showed that the ester
functionality of butyryl-salicylic acid was crucial and associated
with the acylation of key bacterial virulence factors and metabolic
enzymes, which are important for Salmonella infection
of host cells and bacterial growth. Beyond the Gram-negative bacterial
pathogens, butyryl-salicylic acid also showed better antibacterial
activity compared to aspirin against Clostridioides difficile, a clinically challenging Gram-positive bacterial pathogen. Notably,
coadministration of butyryl-salicylic acid, but not aspirin, effectively
attenuated Salmonella pathogenesis in vivo. This study highlights how the analysis of microbiota metabolite
mechanisms may inspire the repurposing and development of new anti-infective
agents.