title: Pentamidine sensitizes Gram-negative pathogens to antibiotics and overcomes acquired colistin resistance.
abstract: The increasing use of polymyxins1in 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 lipopolysaccharide3. Thus, new strategies are needed to address the rapidly diminishing number of treatment options for Gram-negative infections4. 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 antibiotics5. 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 pentamidine6as 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.
authors.affiliation: Michael G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8N 3Z5, Canada.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Stokes
authors.affiliation: Michael G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8N 3Z5, Canada.
authors.forename: Craig R
authors.initials: CR
authors.lastname: MacNair
authors.affiliation: Michael G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8N 3Z5, Canada.
authors.forename: Bushra
authors.initials: B
authors.lastname: Ilyas
authors.affiliation: Michael G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8N 3Z5, Canada.
authors.forename: Shawn
authors.initials: S
authors.lastname: French
authors.affiliation: Michael G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8N 3Z5, Canada.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Côté
authors.affiliation: Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario N1G 2W1, Canada.
authors.forename: Catrien
authors.initials: C
authors.lastname: Bouwman
authors.affiliation: Michael G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8N 3Z5, Canada.
authors.forename: Maya A
authors.initials: MA
authors.lastname: Farha
authors.affiliation: Michael G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8N 3Z5, Canada.
authors.forename: Arthur O
authors.initials: AO
authors.lastname: Sieron
authors.affiliation: Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario N1G 2W1, Canada.
authors.forename: Chris
authors.identifier: http://orcid.org/0000-0002-5267-7027
authors.initials: C
authors.lastname: Whitfield
authors.affiliation: Michael G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8N 3Z5, Canada.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Coombes
authors.affiliation: Michael G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8N 3Z5, Canada.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Brown
mesh_terms: D000151:Acinetobacter Infections / Q000382:microbiology; D040981:Acinetobacter baumannii / Q000187:drug effects; D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism*; D003091:Colistin / Q000378:metabolism*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D024881:Drug Resistance, Bacterial; D004357:Drug Synergism; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D010419:Pentamidine / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D010419:Pentamidine; D003091:Colistin