Pyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps

被引：47

作者：

Ple, Coline ^{[1
]}

Tam, Heng-Keat ^{[2
,5
]}

Da Cruz, Anais Vieira ^{[3
]}

Compagne, Nina ^{[3
]}

Jimenez-Castellanos, Juan-Carlos ^{[1
]}

Mueller, Reinke T. ^{[2
]}

Pradel, Elizabeth ^{[1
]}

Foong, Wuen Ee ^{[2
]}

Malloci, Giuliano ^{[4
]}

Ballee, Alexia ^{[3
]}

Kirchner, Moritz A. ^{[2
]}

Moshfegh, Parisa ^{[3
]}

Herledan, Adrien ^{[3
]}

Herrmann, Andrea ^{[2
]}

Deprez, Benoit ^{[3
]}

Willand, Nicolas ^{[3
]}

Vargiu, Attilio Vittorio ^{[4
]}

Pos, Klaas M. ^{[2
]}

Flipo, Marion ^{[3
]}

Hartkoorn, Ruben C. ^{[1
]}

机构：

[1] Univ Lille, U1019 UMR 9017 CIIL Ctr Infect & Immun Lille, Inst Pasteur Lille, CNRS,INSERM,CHU Lille, F-59000 Lille, France

[2] Goethe Univ Frankfurt, Inst Biochem, Max von Laue Str 9, D-60438 Frankfurt, Germany

[3] Univ Lille, Inst Pasteur Lille, INSERM, U1177 Drugs & Mol Living Syst, F-59000 Lille, France

[4] Univ Cagliari, Dept Phys, I-09042 Monserrato, Cagliari, Italy

[5] Univ South China, Hengyang Med Sch, Hengyang 421002, Hunan, Peoples R China

来源：

NATURE COMMUNICATIONS | 2022年 / 13卷 / 01期

基金：

欧盟地平线“2020”;

关键词：

PSEUDOMONAS-AERUGINOSA; SUBSTRATE TRANSPORT; MOLECULAR-DYNAMICS; CRYSTAL-STRUCTURES; ESCHERICHIA-COLI; STRUCTURAL BASIS; BINDING POCKET; ACRB; RESISTANCE; IDENTIFICATION;

D O I：

10.1038/s41467-021-27726-2

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Efflux transporters of the RND family confer resistance to multiple antibiotics in Gramnegative bacteria. Here, we identify and chemically optimize pyridylpiperazine-based compounds that potentiate antibiotic activity in E. coli through inhibition of its primary RND transporter, AcrAB-TolC. Characterisation of resistant E. coli mutants and structural biology analyses indicate that the compounds bind to a unique site on the transmembrane domain of the AcrB L protomer, lined by key catalytic residues involved in proton relay. Molecular dynamics simulations suggest that the inhibitors access this binding pocket from the cytoplasm via a channel exclusively present in the AcrB L protomer. Thus, our work unveils a class of allosteric efflux-pump inhibitors that likely act by preventing the functional catalytic cycle of the RND pump.

引用

页数：11