Small molecule resensitizesSalmonellato itaconate and decreases bacterial proliferation in macrophages

Abstract

Antimicrobial resistance is a global health crisis offering little reprieve. The situation urgently calls for new drug targets and therapies for infections. We have previously suggested a different approach to treat infections, termed bacterio-modulation, in which a compound modulates the bacterial response to the host immune defense. Herein we show that monocytes infected with Salmonella enterica spp. Typhimurium can be cured using non-antimicrobial compounds that resensitize the bacterium to itaconate, a macrophage-derived antimicrobial metabolite. We propose that this represents a novel strategy to treat infections.

Itaconate: an antimicrobial metabolite of macrophages

“…78 This compound has also shown effectiveness in clearing S. Typhimurium in macrophage cells. 122 Compound 1 cannot be used in vivo, however, because it is rapidly cleaved by serum proteins called pantetheinases. This vulnerability has long plagued the development of pantothenamides, but there has been recent progress in identifying pantothenamide analogues that are pantetheinase-resistant while retaining biological activity.…”