Williams John D, Torhan Matthew C, Neelagiri Venugopal R, Brown Carson, Bowlin Nicholas O, Di Ming, McCarthy Courtney T, Aiello Daniel, Peet Norton P, Bowlin Terry L, Moir Donald T
Microbiotix, Inc., Worcester, MA 01605, United States.
Microbiotix, Inc., Worcester, MA 01605, United States.
Bioorg Med Chem. 2015 Mar 1;23(5):1027-43. doi: 10.1016/j.bmc.2015.01.011. Epub 2015 Jan 13.
The increasing prevalence of drug-resistant bacterial infections is driving the discovery and development not only of new antibiotics, but also of inhibitors of virulence factors that are crucial for in vivo pathogenicity. One such virulence factor is the type III secretion system (T3SS), which plays a critical role in the establishment and dissemination of Pseudomonas aeruginosa infections. We have recently described the discovery and characterization of a series of inhibitors of P. aeruginosa T3SS based on a phenoxyacetamide scaffold. To better characterize the factors involved in potent T3SS inhibition, we have conducted a systematic exploration of this structure, revealing several highly responsive structure-activity relationships indicative of interaction with a specific target. Most of the structural features contributing to potency were additive, and combination of those features produced optimized inhibitors with IC50 values <1μM.
耐药细菌感染的日益普遍不仅推动了新型抗生素的发现和开发，也推动了对体内致病性至关重要的毒力因子抑制剂的发现和开发。III型分泌系统（T3SS）就是这样一种毒力因子，它在铜绿假单胞菌感染的建立和传播中起着关键作用。我们最近描述了一系列基于苯氧乙酰胺支架的铜绿假单胞菌T3SS抑制剂的发现和特性。为了更好地表征强效T3SS抑制所涉及的因素，我们对该结构进行了系统探索，揭示了几个高度响应的构效关系，表明与特定靶点相互作用。大多数有助于效力的结构特征是累加性的，这些特征的组合产生了IC50值<1μM的优化抑制剂。
