Tony Velkov
University of Melbourne, Australia
Title: From breast cancer to antimicrobial: Combating extremely-resistant Gram-negative superbugs using novel combinations of polymyxin B with selective estrogen receptor modulators
Biography
Biography: Tony Velkov
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 micro dilution 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 (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 GFP release, cytoplasmic membrane depolarization, permeabilizing activity in a nitrocefin assay and an increase of cellular reactive oxygen species from P. aeruginosa cells. Additionally, 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 to 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 due to problematic XDR Gram-negatives.