Pentamidine sensitizes Gram-negative pathogens to antibiotics and overcomes acquired colistin resistance.
Jonathan M StokesCraig R MacNairBushra IlyasShawn FrenchJean-Philippe CôtéCatrien BouwmanMaya A FarhaArthur O SieronChris WhitfieldBrian K CoombesEric D BrownPublished in: Nature microbiology (2017)
The increasing use of polymyxins1 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 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 pentamidine6 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.
Keyphrases
- gram negative
- multidrug resistant
- acinetobacter baumannii
- drug resistant
- klebsiella pneumoniae
- escherichia coli
- toll like receptor
- early stage
- pseudomonas aeruginosa
- adipose tissue
- crispr cas
- oxidative stress
- risk assessment
- lps induced
- molecular docking
- drug induced
- climate change
- molecular dynamics simulations
- type diabetes
- metabolic syndrome
- high throughput
- mass spectrometry
- adverse drug