Synthesis and structure-activity relationships of novel phenoxyacetamide inhibitors of the Pseudomonas aeruginosa type III secretion system (T3SS)

被引：32

作者：

Williams, John D. ^{[1
]}

Torhan, Matthew C. ^{[1
]}

Neelagiri, Venugopal R. ^{[1
]}

Brown, Carson ^{[1
]}

Bowlin, Nicholas O. ^{[1
]}

Di, Ming ^{[1
]}

McCarthy, Courtney T. ^{[1
]}

Aiello, Daniel ^{[1
]}

Peet, Norton P. ^{[1
]}

Bowlin, Terry L. ^{[1
]}

Moir, Donald T. ^{[1
]}

机构：

[1] Microbiotix Inc, Worcester, MA 01605 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2015年 / 23卷 / 05期

基金：

美国国家卫生研究院;

关键词：

Type III secretion system; Virulence factor; Pseudomonas aeruginosa; Phenoxyacetamide; Mitsunobu reaction; BACTERIAL VIRULENCE; VENTILATED PATIENTS; ANTIBIOTICS; INFECTION; CHALLENGES; RESISTANCE; TARGET; DRUGS;

D O I：

10.1016/j.bmc.2015.01.011

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 <1 mu M. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：1027 / 1043

页数：17

共 33 条

[1] Discovery and Characterization of Inhibitors of Pseudomonas aeruginosa Type III Secretion [J].