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
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(Published version)
Date
2023
Authors
Kaul, L.
Abdo, A.I.
Coenye, T.
Swift, S.
Zannettino, A.
Süss, R.
Richter, K.
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Journal article
Citation
Biofilms, 2023; 5:100130-1-100130-10
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Laurine Kaul, Adrian I. Abdo, Tom Coenye, Simon Swift, Andrew Zannettino, Regine Süss, Katharina Richter
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Abstract
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.
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Dissertation Note
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Available online 17 May 2023
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© 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).