Identification of new terpenoids and development of novel HyalUronic acid-monoterpenoid conjugates for the treatment and tissue regeneration of SKin infections caused bY antibiotic-resistant bacteria.

This project regards the sector of wound and infected wound care. Wound infections are clinical entities of variable presentation, etiology and severity that involve microbial invasion of the layers of the skin and underlying soft tissues. Moreover the ever-present problem of antimicrobial resistance, is made worse by antibiotic exposure or prolonged hospitalization. The situation with both wound infections and multidrug-resistance is particularly grave in long-term care facilities and affects many patients, with older people more than others. The consequent socioeconomic burden is immense and urge basic and applied research efforts to be overcome. This proposal focuses on the development of novel hyaluronic acid-monoterpene conjugates (HAMCs) endowed with promising properties for tissue repair and antimicrobial action, even in the presence of multi-drug resistant pathogens. Their nature and mechanism of action increase the likelihood that no resistance or cross-resistance to known antibiotics will rapidly arise and that microbial biofilms may also be inhibited. In detail, the study has the following objectives: 1. To satisfy the increasing demand for new anti-infective approaches to overcome the mounting threat of multiple-resistant pathogenic bacteria responsible for many severe and complicated infections. Objective 1 represents the general framework of the present project. 2. To investigate both the antimicrobial and the regenerative activity of novel HAMCs of well-studied monoterpens such as eugenol, carvacrol and thymol. This objective is critical, also in view of the paucity in the number of new molecules feeding the antimicrobial development pipeline. After the selection of the formulations with the highest antimicrobial activity, we will proceed by performing toxicological studies on animal and/or human cell lines and in vivo experiments in animal models of skin or wound infections. 3. To search for new terpenoids with similar desirable properties among the largely unexplored world of bacterial terpenoids, which counts an interesting, albeit relatively low, number of molecules with antimicrobial, antioxidant, and anti-inflammatory activities. A large collection of environmental bacterial species available in the laboratory of the proposing team will be the starting point for the investigation of the bacterial terpenomes and the associated genomes. These latter will be also mined to search for the basic structural features of terpenoids’ synthesis-associated gene clusters. We believe that this part of the project could offer the opportunity to open the way to a better exploitation of the microbial terpenoids in medicinal chemistry, pharmacology, and clinical microbiology.