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.

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.
Journal	Science Translational Medicine
Pages
Volume	14
Date	1/01/2022
Grant ID
Funding Body
URL	http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1126/scitranslmed.abn3758