From Breast Cancer to Antimicrobial: Combating Extremely Resistant Gram-Negative "superbugs" Using Novel Combinations of Polymyxin B with Selective Estrogen Receptor Modulators

Maytham H. Hussein, Elena K. Schneider, Alysha G. Elliott, Meiling Han, Felisa Reyes-Ortega, Faye Morris, Mark A. T. Blastovich, Raad Jasim, Bart Currie, Mark Mayo, Mark Baker, Matthew A. Cooper, Jian Li, Tony Velkov

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)640-650
Number of pages11
JournalMicrobial Drug Resistance
Volume23
Issue number5
Early online date9 Dec 2016
DOIs
Publication statusPublished - 1 Jul 2017

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Hussein, M. H., Schneider, E. K., Elliott, A. G., Han, M., Reyes-Ortega, F., Morris, F., Blastovich, M. A. T., Jasim, R., Currie, B., Mayo, M., Baker, M., Cooper, M. A., Li, J., & Velkov, T. (2017). From Breast Cancer to Antimicrobial: Combating Extremely Resistant Gram-Negative "superbugs" Using Novel Combinations of Polymyxin B with Selective Estrogen Receptor Modulators. Microbial Drug Resistance, 23(5), 640-650. https://doi.org/10.1089/mdr.2016.0196