Endogenous Enzymes Enable Antimicrobial Activity.

In light of the continued threat of antimicrobial-resistant bacteria, new strategies to expand the repertoire of antimicrobial compounds are necessary. Prodrugs are an underexploited strategy in this effort. Here, we report on the enhanced antimicrobial activity of a prodrug toward bacteria having an enzyme capable of its activation. A screen led us to the sulfurol ester of the antibiotic -3-(4-chlorobenzoyl)acrylic acid. An endogenous esterase makes sensitive to this prodrug. Candidate esterases were identified, and their heterologous production made sensitive to the ester prodrug. Taken together, these data suggest a new approach to the development of antimicrobial compounds that takes advantage of endogenous enzymatic activities to target specific bacteria.