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- Title
Topical, immunomodulatory epoxy-tiglianes induce biofilm disruption and healing in acute and chronic skin wounds.
- Authors
Powell, Lydia C.; Cullen, Jason K.; Boyle, Glen M.; De Ridder, Tom; Yap, Pei-Yi; Xue, Wenya; Pierce, Carly J.; Pritchard, Manon F.; Menzies, Georgina E.; Abdulkarim, Muthanna; Adams, Jennifer Y. M.; Stokniene, Joana; Francis, Lewis W.; Gumbleton, Mark; Johns, Jenny; Hill, Katja E.; Jones, Adam V.; Parsons, Peter G.; Reddell, Paul; Thomas, David W.
- Abstract
The management of antibiotic-resistant, bacterial biofilm infections in chronic skin wounds is an increasing clinical challenge. Despite advances in diagnosis, many patients do not derive benefit from current anti-infective/antibiotic therapies. Here, we report a novel class of naturally occurring and semisynthetic epoxy-tiglianes, derived from the Queensland blushwood tree (Fontainea picrosperma), and demonstrate their antimicrobial activity (modifying bacterial growth and inducing biofilm disruption), with structure/activity relationships established against important human pathogens. In vitro, the lead candidate EBC-1013 stimulated protein kinase C (PKC)–dependent neutrophil reactive oxygen species (ROS) induction and NETosis and increased expression of wound healing–associated cytokines, chemokines, and antimicrobial peptides in keratinocytes and fibroblasts. In vivo, topical EBC-1013 induced rapid resolution of infection with increased matrix remodeling in acute thermal injuries in calves. In chronically infected diabetic mouse wounds, treatment induced cytokine/chemokine production, inflammatory cell recruitment, and complete healing (in six of seven wounds) with ordered keratinocyte differentiation. These results highlight a nonantibiotic approach involving contrasting, orthogonal mechanisms of action combining targeted biofilm disruption and innate immune induction in the treatment of chronic wounds. Understanding antibiofilm activity: Bacterial biofilms pose a therapeutic challenge to managing chronic wounds and contribute to antimicrobial resistance. Here, Powell et al. investigated the structure/activity relationships of epoxy-tigliane compounds derived from the blushwood tree with respect to their role in wound healing. The compounds interacted with the cell wall of bacteria but showed variable permeabilization in Gram-negative versus Gram-positive cultures. They disrupted established biofilms by interacting with the extracellular polymeric substance matrix, activated immune cells to induce reactive oxygen species, and promoted wound healing in infected thermal injuries in calves when applied topically. In chronic wounds in diabetic mice, the semisynthetic compound EBC-1013 up-regulated host-defense peptides, altered cytokine expression, activated immune cells, and led to greater wound closure. Results help uncover the mechanism by which epoxy-tiglianes promote wound healing and support further development of EBC-1013.
- Subjects
QUEENSLAND; CHRONIC wounds &; injuries; SKIN injuries; HEALING; PROTEIN kinase C; BACTERIAL cell walls; FIBROBLASTS; KERATINOCYTE differentiation
- Publication
Science Translational Medicine, 2022, Vol 14, Issue 662, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.abn3758