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 journalArticleResearchpeer-review

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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Selective Estrogen Receptor Modulators
Polymyxin B
Toremifene
Pseudomonas aeruginosa
Breast Neoplasms
Polymyxins
Acinetobacter baumannii
Klebsiella pneumoniae
Bacterial Load
Microbial Sensitivity Tests
Tamoxifen
Biofilms
Cross Infection
Sputum
Reactive Oxygen Species
Fluorescence
Cell Membrane
Electrons
Membranes

Cite this

Hussein, Maytham H. ; Schneider, Elena K. ; Elliott, Alysha G. ; Han, Meiling ; Reyes-Ortega, Felisa ; Morris, Faye ; Blastovich, Mark A. T. ; Jasim, Raad ; Currie, Bart ; Mayo, Mark ; Baker, Mark ; Cooper, Matthew A. ; Li, Jian ; Velkov, Tony. / From Breast Cancer to Antimicrobial : Combating Extremely Resistant Gram-Negative "superbugs" Using Novel Combinations of Polymyxin B with Selective Estrogen Receptor Modulators. In: Microbial Drug Resistance. 2017 ; Vol. 23, No. 5. pp. 640-650.
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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.",
keywords = "Gram-negative, multidrug resistant, polymyxin, repositioning, SERMs",
author = "Hussein, {Maytham H.} and Schneider, {Elena K.} and Elliott, {Alysha G.} and Meiling Han and Felisa Reyes-Ortega and Faye Morris and Blastovich, {Mark A. T.} and Raad Jasim and Bart Currie and Mark Mayo and Mark Baker and Cooper, {Matthew A.} and Jian Li and Tony Velkov",
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Hussein, MH, Schneider, EK, Elliott, AG, Han, M, Reyes-Ortega, F, Morris, F, Blastovich, MAT, Jasim, R, Currie, B, Mayo, M, Baker, M, Cooper, MA, 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, vol. 23, no. 5, pp. 640-650. https://doi.org/10.1089/mdr.2016.0196

From Breast Cancer to Antimicrobial : Combating Extremely Resistant Gram-Negative "superbugs" Using Novel Combinations of Polymyxin B with Selective Estrogen Receptor Modulators. / Hussein, Maytham H.; Schneider, Elena K.; Elliott, Alysha G.; Han, Meiling; Reyes-Ortega, Felisa; Morris, Faye; Blastovich, Mark A. T.; Jasim, Raad; Currie, Bart; Mayo, Mark; Baker, Mark; Cooper, Matthew A.; Li, Jian; Velkov, Tony.

In: Microbial Drug Resistance, Vol. 23, No. 5, 01.07.2017, p. 640-650.

Research output: Contribution to journalArticleResearchpeer-review

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