In vitro and in vivo evaluation of diethyldithiocarbamate with copper ions and its liposomal formulation for the treatment of Staphylococcus aureus and Staphylococcus epidermidis biofilms
Laurine Kaul,
Adrian I. Abdo,
Tom Coenye,
Simon Swift,
Andrew Zannettino,
Regine Süss,
Katharina Richter
Affiliations
Laurine Kaul
Richter Lab, Department of Surgery, Basil Hetzel Institute for Translational Health Research, University of Adelaide, 37 Woodville Road, Adelaide, SA, 5011, Australia; Institute of Pharmaceutical Sciences, Department of Pharmaceutics, University of Freiburg, Sonnenstr. 5, 79104, Freiburg, Germany; Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, 4 North Terrace, Adelaide, SA, 5000, Australia; Corresponding author. Richter Lab, Department of Surgery, Basil Hetzel Institute for Translational Health Research, University of Adelaide, 37 Woodville Road, Adelaide, SA, 5011, Australia.
Adrian I. Abdo
Richter Lab, Department of Surgery, Basil Hetzel Institute for Translational Health Research, University of Adelaide, 37 Woodville Road, Adelaide, SA, 5011, Australia; Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, 4 North Terrace, Adelaide, SA, 5000, Australia
Department of Molecular Medicine and Pathology, University of Auckland, 85 Park Road, Grafton, Auckland, 1023, New Zealand
Andrew Zannettino
Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, 4 North Terrace, Adelaide, SA, 5000, Australia; Precision Cancer Medicine Theme, South Australian Health & Medical Research Institute, North Terrace, Adelaide, SA, Australia; Central Adelaide Local Health Network, Adelaide, Australia
Regine Süss
Institute of Pharmaceutical Sciences, Department of Pharmaceutics, University of Freiburg, Sonnenstr. 5, 79104, Freiburg, Germany
Katharina Richter
Richter Lab, Department of Surgery, Basil Hetzel Institute for Translational Health Research, University of Adelaide, 37 Woodville Road, Adelaide, SA, 5011, Australia; Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, 4 North Terrace, Adelaide, SA, 5000, Australia; Institute for Photonics and Advanced Sensing, University of Adelaide, Adelaide, Australia
Surgical site infections (SSIs) are mainly caused by Staphylococcus aureus (S. aureus) and Staphylococcus epidermidis (S. epidermidis) biofilms. Biofilms are aggregates of bacteria embedded in a self-produced matrix that offers protection against antibiotics and promotes the spread of antibiotic-resistance in bacteria. Consequently, antibiotic treatment frequently fails, resulting in the need for alternative therapies. The present study describes the in vitro efficacy of the Cu(DDC)2 complex (2:1 M ratio of diethyldithiocarbamate (DDC−) and Cu2+) with additional Cu2+ against S. aureus and S. epidermidis biofilms in models mimicking SSIs and in vitro antibacterial activity of a liposomal Cu(DDC)2 + Cu2+ formulation. The in vitro activity on S. aureus and S. epidermidis biofilms grown on two hernia mesh materials and in a wound model was determined by colony forming unit (CFU) counting. Cu2+-liposomes and Cu(DDC)2-liposomes were prepared, and their antibacterial activity was assessed in vitro using the alamarBlue assay and CFU counting and in vivo using a Galleria mellonella infection model. The combination of 35 μM DDC− and 128 μM Cu2+ inhibited S. aureus and S. epidermidis biofilms on meshes and in a wound infection model. Cu(DDC)2-liposomes + free Cu2+ displayed similar antibiofilm activity to free Cu(DDC)2 + Cu2+, and significantly increased the survival of S. epidermidis-infected larvae. Whilst Cu(DDC)2 + Cu2+ showed substantial antibiofilm activity in vitro against clinically relevant biofilms, its application in mammalian in vivo models is limited by solubility. The liposomal Cu(DDC)2 + Cu2+ formulation showed antibiofilm activity in vitro and antibacterial activity and low toxicity in G. mellonella, making it a suitable water-soluble formulation for future application on infected wounds in animal trials.
