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.

An integrative, multi-omics approach towards the prioritization of Klebsiella pneumoniae drug targets

“…Indeed, in vitro tests combining PB and the carbapenem tigecycline using a hollow-fiber infection model have shown a bactericidal effect against CRE while suppressing the emergence of PB resistance 76 . Also, a combination of PB with a non-antibiotic drug like selective estrogen receptor modulators (SERMs) demonstrated excellent antibacterial killing kinetics against polymyxin-resistant P. aeruginosa, A. baumannii , and K. pneumoniae 77 . Given the benefit of polymyxin combination therapy, future studies could be performed to validate the activity of other polymyxin-based combinations, such as those described hereinafter.…”

Aminoglycoside Concentrations Required for Synergy with Carbapenems against Pseudomonas aeruginosa Determined via Mechanistic Studies and Modeling

“…Confocal imaging. Confocal imaging was performed to quantify the signal from cytosolic GFP; as described previously (55,56), damage to the outer membrane can cause an extensive loss of GFP and thus decreased fluorescence intensity from cytosolic GFP. In brief, bacterial cells were grown on chamber slides and treated for 2 h with monotherapies and combinations of imipenem (4 mg/liter) and tobramycin (16 mg/liter and 32 mg/liter) at 37°C.…”

Synergistic Killing of Polymyxin B in Combination With the Antineoplastic Drug Mitotane Against Polymyxin-Susceptible and -Resistant Acinetobacter baumannii: A Metabolomic Study

“…Recently, the combination of an antibiotic (including polymyxins) and non-antibiotic drug has emerged as a potentially valuable and cost-effective approach to improve the clinical efficacy of currently available antibiotics against problematic MDR bacterial pathogens ( Ejim et al, 2011 ; Hussein et al, 2016 ; Schneider et al, 2016 , 2017 ). In a recent study, we demonstrated that the combination of clinically achievable concentrations of polymyxin B (2 mg/L) and the antineoplastic agent mitotane (4 mg/L) provided enhanced antimicrobial activity against MDR as well as polymyxin-resistant A. baumannii ( Tran et al, 2018 ).…”