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 J Currie, Mark Mayo, Mark Baker, Matthew A Cooper, Jian Li, Tony Velkov

Research output: Contribution to journalArticleResearchpeer-review

13 Citations (Scopus)

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
DOIs
Publication statusPublished - 1 Jul 2017

Keywords

  • Gram-negative
  • multidrug resistant
  • polymyxin
  • repositioning
  • SERMs

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 J ; 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.",
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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 Currie, {Bart J} 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, BJ, 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 J; 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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AU - Elliott, Alysha G

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AB - 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.

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