Fluopsin C for treating multidrug-resistant infections: In vitro activity aganist clinically important strains and in vivo efficacy against carbapenemase-producing Klebsiella pneumoniae

The increasing emergence of multidrug-resistant (MDR) organisms in hospital infectionsis causing a global public health crisis. The development of drugs with effective antibioticaction against such agents is of the highest priority. In the present study, the actionof Fluopsin C against MDR clinical isolates was evaluated underin vitroandin vivoconditions. Fluopsin C was produced in cell suspension culture ofPseudomonasaeruginosaLV strain, purified by liquid adsorption chromatography and identified bymass spectrometric analysis. Bioactivity, bacterial resistance development risk againstclinically important pathogenic strains and toxicity in mammalian cell were initiallydetermined byin vitromodels.In vivotoxicity was evaluated inTenebrio molitorlarvae and mice. The therapeutic efficacy of intravenous Fluopsin C administration wasevaluated in a murine model ofKlebsiella pneumoniae(KPC) acute sepsis, using sixdifferent treatments. Thein vitroresults indicated MIC and MBC below 2μg/mL and lowbacterial resistance development frequency. Electron microscopy showed that FluopsinC may have altered the exopolysaccharide matrix and caused disruption of the cell wallof MDR bacteria. Best therapeutic results were achieved in mice treated with a singledose 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 andmoderate hepatotoxicity. The results demonstrated the efficacy of Fluopsin C againstMDR organisms inin vitroandin vivomodels, and hence it can be a novel therapeuticagent for the control of severe MDR infections