Structure–activity relationship study of benserazide derivatives as PilB inhibitors

Abstract

Antimicrobial resistance is an imminent health threat worldwide. Development of alternative treatments for drug-resistant microbes is of paramount importance. Targeting virulence factors, such as the type IV pilus construction enzyme PilB, is a strategy of treatment. Recently, we reported the discovery of a potent inhibitor of PilB, the FDA approved drug benserazide (IC₅₀ = 3.68 μM). Herein, we report the structure–activity relationship profiling of benserazide analogues and identify key moieties that enable PilB inhibition. We found that bis-hydroxyl groups on the ortho position of the aryl ring, a rigid imine, and exchange of the serine for a thiol have resulted in marked improvement in potency. Our studies identified 11c as a PilB inhibitor with an IC₅₀ of 580 nM and selectivity for PilB over an unrelated ATPase, apyrase. These compounds provide the chemical tools to validate virulence factors as antibacterial mechanisms of action.