Fluopsin C for Treating Multidrug-Resistant Infections: In vitro Activity Against Clinically Important Strains and in vivo Efficacy Against Carbapenemase-Producing Klebsiella pneumoniae

Abstract

The increasing emergence of multidrug-resistant (MDR) organisms in hospital infections is causing a global public health crisis. The development of drugs with effective antibiotic action against such agents is of the highest priority. In the present study, the action of Fluopsin C against MDR clinical isolates was evaluated under <i>in vitro</i> and <i>in vivo</i> conditions. Fluopsin C was produced in cell suspension culture of <i>Pseudomonas aeruginosa</i> LV strain, purified by liquid adsorption chromatography and identified by mass spectrometric analysis. Bioactivity, bacterial resistance development risk against clinically important pathogenic strains and toxicity in mammalian cell were initially determined by <i>in vitro</i> models. <i>In vivo</i> toxicity was evaluated in <i>Tenebrio molitor</i> larvae and mice. The therapeutic efficacy of intravenous Fluopsin C administration was evaluated in a murine model of <i>Klebsiella pneumoniae</i> (KPC) acute sepsis, using six different treatments. The <i>in vitro</i> results indicated MIC and MBC below 2 μg/mL and low bacterial resistance development frequency. Electron microscopy showed that Fluopsin C may have altered the exopolysaccharide matrix and caused disruption of the cell wall of MDR bacteria. Best therapeutic results were achieved in mice treated with a single dose of 2 mg/kg and in mice treated with two doses of 1 mg/kg, 8 h apart. Furthermore, acute and chronic histopathological studies demonstrated absent nephrotoxicity and moderate hepatotoxicity. The results demonstrated the efficacy of Fluopsin C against MDR organisms in <i>in vitro</i> and <i>in vivo</i> models, and hence it can be a novel therapeutic agent for the control of severe MDR infections.