Topical, immunomodulatory epoxy-tiglianes induce biofilm disruption and healing in acute and chronic skin wounds

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.

A Review of Immunomodulatory Reprogramming by Probiotics in Combating Chronic and Acute Diabetic Foot Ulcers (DFUs)

“…Epoxy-tiglianes showed an effective degradation of bacterial biofilms by inducing the production of antimicrobial genes (DEFB4 and DEF103A) and leukocyte survival factors (IL-1β, IL-17, CXCL-8, and CCL-20). It also induced protein-kinase-dependent ROS generation, which resulted in enhanced fibroblast and keratinocyte production [113].…”

Hemostatic and Ultrasound-Controlled Bactericidal Silk Fibroin Hydrogel via Integrating a Perfluorocarbon Nanoemulsion

“…Meanwhile, conferring bactericidal capabilities to hydrogels was achieved by incorporating adhesion factors. − These factors enable hydrogels to stick bacteria through intermolecular forces and disrupt their cell structure. Alternatively, hydrogels were formulated to release bacteria-toxic molecules. − Otherwise, hydrogels were combined with bactericidal thermal therapy − or ROS product therapy. − Nonetheless, the hemostatic and bactericidal efficacy may conflict with each other. For instance, stick-killing methods are susceptible to fouling by blood or other autologous biomacromolecules, and the formation of a solid-state blood clot during hemostasis can obstruct drug diffusion.…”

Global trends in research of high-throughput sequencing technology associated with chronic wounds from 2002 to 2022: A bibliometric and visualized study

“…A complex wound microbial environment is an important reason for chronic wound persistence (7,8). Infection is also an important pathogenic factor for sepsis and multiple organ failure in patients with chronic wounds and a major threat to the life of patients with chronic wounds (9)(10)(11)(12). It is currently believed that the bacterial-host interaction may also lead to wound healing damage (8,13).…”