Quinlan Joseph E, Soleymani Ghazal, Shimozono Tori M, Yang Zhaomin, Santos Webster L
Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech Blacksburg VA 24060 USA
Department of Biological Sciences Virginia Tech Blacksburg VA 24060 USA
RSC Adv. 2025 Jun 5;15(24):18986-18999. doi: 10.1039/d5ra02702k. eCollection 2025 Jun 4.
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.
抗菌耐药性是全球迫在眉睫的健康威胁。开发针对耐药微生物的替代治疗方法至关重要。靶向毒力因子，如IV型菌毛构建酶PilB，是一种治疗策略。最近，我们报道了PilB的一种有效抑制剂的发现，即美国食品药品监督管理局（FDA）批准的药物苄丝肼（IC = 3.68 μM）。在此，我们报告苄丝肼类似物的构效关系分析，并确定能够抑制PilB的关键部分。我们发现芳环位置上的双羟基、刚性亚胺以及将丝氨酸替换为硫醇导致了效力的显著提高。我们的研究确定11c为一种PilB抑制剂，IC为580 nM，对PilB的选择性高于无关的ATP酶——腺苷三磷酸双磷酸酶。这些化合物提供了化学工具，以验证毒力因子作为抗菌作用机制。
