Pentamidine sensitizes Gram-negative pathogens to antibiotics and overcomes acquired colistin resistance

被引:263
作者
Stokes, Jonathan M. [1 ]
MacNair, Craig R. [1 ]
Ilyas, Bushra [1 ]
French, Shawn [1 ]
Cote, Jean-Philippe [1 ]
Bouwman, Catrien [2 ]
Farha, Maya A. [1 ]
Sieron, Arthur O. [1 ]
Whitfield, Chris [2 ]
Coombes, Brian K. [1 ]
Brown, Eric D. [1 ]
机构
[1] McMaster Univ, Michael G DeGroote Inst Infect Dis Res, Dept Biochem & Biomed Sci, Hamilton, ON L8N 3Z5, Canada
[2] Univ Guelph, Dept Mol & Cellular Biol, Guelph, ON N1G 2W1, Canada
基金
加拿大健康研究院; 加拿大自然科学与工程研究理事会;
关键词
OUTER-MEMBRANE PERMEABILITY; ESCHERICHIA-COLI; ACINETOBACTER-BAUMANNII; BACTERIAL; AGENTS; DATABASES; SYSTEMS; GROWTH;
D O I
10.1038/nmicrobiol.2017.28
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
The increasing use of polymyxins(1) in addition to the dissemination of plasmid-borne colistin resistance threatens to cause a serious breach in our last line of defence against multidrug-resistant Gram-negative pathogens, and heralds the emergence of truly pan-resistant infections. Colistin resistance often arises through covalent modification of lipid A with cationic residues such as phosphoethanolamine-as is mediated by Mcr-1 (ref. 2)-which reduce the affinity of polymyxins for lipopoly-saccharide(3). Thus, new strategies are needed to address the rapidly diminishing number of treatment options for Gram-negative infections(4). The difficulty in eradicating Gram-negative bacteria is largely due to their highly impermeable outer membrane, which serves as a barrier to many otherwise effective antibiotics(5). Here, we describe an unconventional screening platform designed to enrich for non-lethal, outer-membrane-active compounds with potential as adjuvants for conventional antibiotics. This approach identified the antiprotozoal drug pentamidine(6) as an effective perturbant of the Gram-negative outer membrane through its interaction with lipopolysaccharide. Pentamidine displayed synergy with antibiotics typically restricted to Gram-positive bacteria, yielding effective drug combinations with activity against a wide range of Gram-negative pathogens in vitro, and against systemic Acinetobacter baumannii infections in mice. Notably, the adjuvant activity of pentamidine persisted in polymyxin-resistant bacteria in vitro and in vivo. Overall, pentamidine and its structural analogues represent unexploited molecules for the treatment of Gram-negative infections, particularly those having acquired polymyxin resistance determinants.
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页数:8
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