Structure-activity relationship study of benserazide derivatives as PilB inhibitors.

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 (IC = 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 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 IC 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.