Tamoxifen repurposing to combat infections by multidrug-resistant Gram-negative bacilli

Abstract

AbstractThe development of new strategic therapies for multidrug-resistant bacteria, like the use of non-antimicrobial approaches and/or drugs repurposing to be used as monotherapies or in combination with clinically relevant antibiotics, has become an urgent need. A therapeutic alternative for infections by multidrug-resistant Gram-negative bacilli (MDR-GNB) is immune system modulation to improve the infection clearance. We showed that immunocompetent mice infected by Acinetobacter baumannii, Pseudomonas aeruginosa or Escherichia coli in peritoneal sepsis models and treated with tamoxifen at 80 mg/kg/d for three days reduced the release of MCP-1 and its signalling pathway IL-18 and phosphorylated ERK1/2. This reduction of MCP-1 induced the reduction of migration of inflammatory monocytes and neutrophils from bone marrow to blood. Indeed, the treatment with tamoxifen in murine peritoneal sepsis models reduced the bacterial load in tissues and blood; and increased the mice survival from 0% to 60-100%. Tamoxifen treatment of neutropenic mice infected by these pathogens increased mice survival up to 20-60%. Furthermore, susceptibility and time-kill assays showed that the metabolites of tamoxifen, N-desmethyltamoxifen, hydroxytamoxifen and endoxifen, the three together exhibited MIC90 values of 16 mg/L and were bactericidal against clinical isolates of A. baumannii and E. coli. This antimicrobial activity of tamoxifen metabolites parallels’ an increased membrane permeability of A. baumannii and E. coli without affecting their outer membrane proteins profiles. Together, these data showed that tamoxifen present a therapeutic efficacy against MDR A. baumannii, P. aeruginosa and E. coli in experimental models of infections and can be repurposed as new treatment for GNB infections.ImportanceAntimicrobial resistance in Gram-negative bacilli (GNB) is a global health treat. Drug repurposing, a novel approach involving the search of new indications for FDA approved drugs is gaining interest. Among them, we found the anti-cancer drug tamoxifen, which presents very promising therapeutic efficacy. The current study showed that tamoxifen presents activity in animal models of infection with MDR Acinetobacter baumannii, Pseudomonas aeruginosa and Escherichia coli by modulating the traffic of innate immune system cells and the antibacterial activity presented by its three major metabolites produced in vivo against these GNB. Our results offer a new candidate to be repurposed to treat severe infections caused by these pathogens.