- Title
- From breast cancer to antimicrobial: combating extremely resistant gram-negative "superbugs" using novel combinations of polymyxin B with selective estrogen receptor modulators
- Creator
- Hussein, Maytham H.; Schneider, Elena K.; Baker, Mark; Cooper, Matthew A.; Li, Jian; Velkov, Tony; Elliott, Alysha G.; Han, Meiling; Reyes-Ortega, Felisa; Morris, Faye; Blastovich, Mark A. T.; Jasim, Raad; Currie, Bart; Mayo, Mark
- Relation
- Microbial Drug Resistance Vol. 23, Issue 5, p. 640-650
- Publisher Link
- http://dx.doi.org/10.1089/mdr.2016.0196
- Publisher
- Mary Ann Liebert
- Resource Type
- journal article
- Date
- 2017
- Description
- Novel therapeutic approaches are urgently needed to combat nosocomial infections caused by extremely drug-resistant (XDR) “superbugs.” This study aimed to investigate the synergistic antibacterial activity of polymyxin B in combination with selective estrogen receptor modulators (SERMs) against problematic Gram-negative pathogens. In vitro synergistic antibacterial activity of polymyxin B and the SERMs tamoxifen, raloxifene, and toremifene was assessed using the microdilution checkerboard and static time–kill assays against a panel of Gram-negative isolates. Polymyxin B and the SERMs were ineffective when used as monotherapy against polymyxin-resistant minimum inhibitory concentration ([MIC] ≥8 mg/L) Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii. However, when used in combination, clinically relevant concentrations of polymyxin B and SERMs displayed synergistic killing against the polymyxin-resistant P. aeruginosa, K. pneumoniae, and A. baumannii isolates as demonstrated by a ≥2–3 log10 decrease in bacterial count (CFU/ml) after 24 hours. The combination of polymyxin B with toremifene demonstrated very potent antibacterial activity against P. aeruginosa biofilms in an artificial sputum media assay. Moreover, polymyxin B combined with toremifene synergistically induced cytosolic green fluorescence protein release, cytoplasmic membrane depolarization, permeabilizing activity in a nitrocefin assay, and an increase of cellular reactive oxygen species from P. aeruginosa cells. In addition, scanning and transmission electron micrographs showed that polymyxin B in combination with toremifene causes distinctive damage to the outer membrane of P. aeruginosa cells, compared with treatments with each compound per se. In conclusion, the combination of polymyxin B and SERMs illustrated a synergistic activity against XDR Gram-negative pathogens, including highly polymyxin-resistant P. aeruginosa isolates, and represents a novel combination therapy strategy for the treatment of infections because of problematic XDR Gram-negative pathogens.
- Subject
- SERMs; repositioning; gram-negative; polymyxin; multidrug resistant
- Identifier
- http://hdl.handle.net/1959.13/1397535
- Identifier
- uon:34293
- Identifier
- ISSN:1076-6294
- Language
- eng
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