Manganese complex [Mn(CO)3(tpa-κ3N)]Br increases antibiotic sensitivity in multidrug-resistant Streptococcus pneumoniae

Objectives: The emergence of multidrug resistance in Streptococcus pneumoniae clones and non-vaccine serotypes has necessitated the development of novel treatment strategies. This work aimed to determine the efficacy of the manganese complex [Mn(CO)(3)(tpa-kappa N-3)]Br against clinically important multidrug-resistant (MDR) S. pneumoniae strains. Methods: Twenty MDR clinical S. pneumoniae strains were included in this study. Minimum inhibitory concentrations (MICs) of [Mn(CO)(3)(tpa-kappa N-3)]Br were determined by broth microdilution alone and in combination with other antimicrobials using chequerboard and/or disk diffusion assays. In vitro efficacy was assessed by time-kill assays, whilst in vivo efficacy was tested using the Galleria mellonella insect model. Results: [Mn(CO)(3)(tpa-kappa N-3)]Br showed moderate in vitro efficacy against S. pneumoniae coupled with bactericidal activity. Chequerboard and disk diffusion assays showed synergy between [Mn(CO)(3)(tpa-kappa N-3)]Br and tetracycline, and the combination of both agents caused rapid kill kinetics and reduced the MIC below the susceptibility breakpoint of 1 mg/L even for tetracycline-resistant strains. Similar results were observed for the combinations of erythromycin or trimethoprim/sulfamethoxazole with Mn complex. In the G. mellonella infection model, mortality and morbidity rates at 96 h were significantly lower in larvae treated with [Mn(CO)(3)(tpa-kappa N-3)]Br than phosphate-buffered saline, whilst treatment with the tetracycline/Mn complex combination was superior to monotherapy, resulting in significantly lower mortality and morbidity rates (P < 0.049). Conclusion: Our results show that [Mn(CO)(3)(tpa-kappa N-3)]Br has in vitro and in vivo antibacterial activity against clinically relevant S. pneumoniae strains and has the potential to be used in combination with currently available antibiotics to increase their effectiveness against MDR S. pneumoniae. (C) 2020 The Author(s). Published by Elsevier Ltd on behalf of International Society for Antimicrobial Chemotherapy.