Repurposing a neurodegenerative disease drug to treat Gram-negative antibiotic-resistant bacterial sepsis
David MP De Oliveira, Lisa Bohlmann, Trent Conroy, Freda E-C Jen, Arun Everest-Dass, Karl A Hansford, Raghu Bolisetti, Ibrahim M El-Deeb, Brian M Forde, Phan Minh-Duy, Jake A Lacey, Aimee Tan, Tania Rivera-Hernandez, Stephan Brouwer, Nadia Keller, Timothy J Kidd, Amanda J Cork, Michelle J Bauer, Gregory M Cook, Mark R Davies Show all
Science Translational Medicine | AMER ASSOC ADVANCEMENT SCIENCE | Published : 2020
The emergence of polymyxin resistance in carbapenem-resistant and extended-spectrum β-lactamase (ESBL)-producing bacteria is a critical threat to human health, and alternative treatment strategies are urgently required. We investigated the ability of the hydroxyquinoline analog ionophore PBT2 to restore antibiotic sensitivity in polymyxin-resistant, ESBL-producing, carbapenem-resistant Gram-negative human pathogens. PBT2 resensitized Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa to last-resort polymyxin class antibiotics, including the less toxic next-generation polymyxin derivative FADDI-287, in vitro. We were unable to select for mutants resis..View full abstract
Awarded by National Health and Medical Research Council of Australia
Awarded by Swiss National Science Foundation
M.J.W., M.A.S., and T.J.K. are recipients of National Health and Medical Research Council of Australia Fellowships. C.A.M. is a recipient of an Australian Research Council Future Fellowship. This work was supported by the National Health and Medical Research Council of Australia (GNT1176180 to M.J.W., M.v.I., M.J.B., and M.A.S.; GNT1071659 to M.J.W., M.v.I., and M.P.J.; and GNT1194130 to M.J.W.). N.K.'s salary was funded by the Swiss National Science Foundation (P2ZHP3_191292).