title: From Breast Cancer to Antimicrobial: Combating Extremely Resistant Gram-Negative "Superbugs" Using Novel Combinations of Polymyxin B with Selective Estrogen Receptor Modulators.
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.
authors.affiliation: 1 Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Australia .
authors.forename: Maytham H
authors.initials: MH
authors.lastname: Hussein
authors.affiliation: 1 Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Australia .
authors.forename: Elena K
authors.initials: EK
authors.lastname: Schneider
authors.affiliation: 2 Institute for Molecular Bioscience, The University of Queensland , Brisbane, Australia .
authors.forename: Alysha G
authors.initials: AG
authors.lastname: Elliott
authors.affiliation: 1 Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Australia .
authors.forename: Meiling
authors.initials: M
authors.lastname: Han
authors.affiliation: 1 Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Australia .
authors.forename: Felisa
authors.initials: F
authors.lastname: Reyes-Ortega
authors.affiliation: 1 Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Australia .
authors.forename: Faye
authors.initials: F
authors.lastname: Morris
authors.affiliation: 2 Institute for Molecular Bioscience, The University of Queensland , Brisbane, Australia .
authors.forename: Mark A T
authors.initials: MAT
authors.lastname: Blastovich
authors.affiliation: 1 Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Australia .
authors.forename: Raad
authors.initials: R
authors.lastname: Jasim
authors.affiliation: 3 Menzies School of Health Research , Casuarina, Australia .
authors.forename: Bart
authors.initials: B
authors.lastname: Currie
authors.affiliation: 3 Menzies School of Health Research , Casuarina, Australia .
authors.forename: Mark
authors.initials: M
authors.lastname: Mayo
authors.affiliation: 4 Priority Research Centre in Reproductive Science, School of Environmental and Life Sciences, University of Newcastle , Callaghan, Australia .
authors.forename: Mark
authors.initials: M
authors.lastname: Baker
authors.affiliation: 2 Institute for Molecular Bioscience, The University of Queensland , Brisbane, Australia .
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Cooper
authors.affiliation: 5 Department of Microbiology, Monash Biomedicine Discovery Institute, Monash University , Parkville, Australia .
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: 1 Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Australia .
authors.forename: Tony
authors.initials: T
authors.lastname: Velkov
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects / Q000254:growth & development / Q000648:ultrastructure; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects* / Q000254:growth & development; D002463:Cell Membrane Permeability / Q000187:drug effects; D058492:Drug Repositioning; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects / Q000235:genetics; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000254:growth & development / Q000648:ultrastructure; D008826:Microbial Sensitivity Tests; D011112:Polymyxin B / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000254:growth & development / Q000648:ultrastructure; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology*; D017312:Toremifene / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D020849:Raloxifene Hydrochloride; D017312:Toremifene; D011112:Polymyxin B
keywords: Gram-negative; SERMs; multidrug resistant; polymyxin; repositioning