Journal
NATURE MICROBIOLOGY
Volume 2, Issue 5, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nmicrobiol.2017.28
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Funding
- Natural Sciences and Engineering Research Council
- Canadian Institutes of Health Research [FDN-143215, MOP-82704, FDN-CEHA-26119]
- Cystic Fibrosis Canada
- Ontario Research Fund
- Michael G. DeGroote Institute for Infectious Disease Research
- Canada Research Chairs Program
- Fonds de reserche en sante du Quebec
- Canadian Institutes of Health Research DSECT Program
- Ontario Graduate Scholarships Program
- Canadian Institutes of Health Research
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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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