Adjuvants Based on Hybrid Antibiotics Overcome Resistance in Pseudomonas aeruginosa and Enhance Fluoroquinolone Efficacy

被引：85

作者：

Gorityala, Bala Kishan ^{[1
]}

Guchhait, Goutam ^{[1
]}

Fernando, Dinesh M. ^{[2
]}

Deo, Soumya ^{[1
]}

McKenna, Sean A. ^{[1
,4
]}

Zhanel, George G. ^{[3
]}

Kumar, Ayush ^{[2
,3
]}

Schweizer, Frank ^{[1
,3
]}

机构：

[1] Univ Manitoba, Dept Chem, Winnipeg, MB R3T 2N2, Canada

[2] Univ Manitoba, Dept Microbiol, Winnipeg, MB R3T 2N2, Canada

[3] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB R3T 1R9, Canada

[4] Dept Biochem & Med Genet, Winnipeg, MB R3T 2N2, Canada

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2016年 / 55卷 / 02期

基金：

加拿大自然科学与工程研究理事会;

关键词：

aminoglycosides; antibiotics; drug design; fluoroquinolones; Pseudomonas aeruginosa; GALLERIA-MELLONELLA; NEAMINE DERIVATIVES; TOBRAMYCIN ANALOGS; EFFLUX PUMP; IDENTIFICATION; INDUCTION; POLYMYXIN; MEMBRANE; PEPTIDES; STRAIN;

D O I：

10.1002/anie.201508330

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

The use of adjuvants that rescue antibiotics against multidrug-resistant (MDR) pathogens is a promising combination strategy for overcoming bacterial resistance. While the combination of beta-lactam antibiotics and beta-lactamase inhibitors has been successful in restoring antibacterial efficacy in MDR bacteria, the use of adjuvants to restore fluoroquinolone efficacy in MDR Gram-negative pathogens has been challenging. We describe tobramycin-ciprofloxacin hybrid adjuvants that rescue the activity of fluoroquinolone antibiotics against MDR and extremely drug-resistant Pseudomonas aeruginosa isolates in vitro and enhance fluoroquinolone efficacy in vivo. Structure-activity studies reveal that the presence of both tobramycin and ciprofloxacin, which are separated by a C12 tether, is critical for the function of the adjuvant. Mechanistic studies indicate that the antibacterial modes of ciprofloxacin are retained while the role of tobramycin is limited to destabilization of the outer membrane in the hybrid.

引用

页码：555 / 559

页数：5

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