Estudo e otimização de uma nova classe de antifúngicos de origem marinha

In recent years, the incidence of life-threatening IFI has markedly risen, placing it as one of the most critical global threats to human health, with an estimated annual fatality count exceeding 1.5 million deaths. The emergence of fungi resistance to current drugs and the epidemiologic shift observed over the last years to fungal species naturally refractory to available antifungal agents has greatly contributed to this unacceptable death toll imposed by IFI [11]. In this context, the development of new strategies to manage IFI, particularly those resistant to available antifungals, has been recently considered by the WHO a top health priority [9]. We will contribute to this global cause by leveraging our recent findings concerning a new marine natural product, specifically a diterpene alkaloid, named SF1, which exhibits outstanding antifungal activity and appears to operate through a new mechanism of action (Fig. 1 and Fig. 2). Using an interdisciplinary approach, we propose to expand the study of SF1 and thoroughly evaluate its antifungal efficacy, safety profile, mechanism of action and production feasibility to accelerate the introduction of a new IFI treatment to the market. Specifically, our objectives are: 1) To establish the chemical synthesis of SF1. SF1 chemical synthesis is expected to be straightforward, cost-effective and easily scalable. Importantly, chemically synthesized compounds may have a smoother path to regulatory approval, expediting the process of bringing new antifungal treatments to market. 2) To demonstrate the superior activity of SF1 compared to current antifungals. We will first assess the spectrum of activity of the compound against other medically important fungi. Having potent antifungal activity, preferably with a new mechanism of action, against hard-to-treat fungal infections can potentially grant SF1 orphan drug designation in the future and attract the interest of pharmaceutical industries. To take the most of SF1 activity, we will also evaluate its antibiofilm potential and synergism with representatives of the three classes of antifungals: fluconazole, caspofungin, and amphotericin B. 3) To synthetize SF1-derivatives with improved antifungal efficacy. The establishment of SF1 chemical synthesis will also offer the opportunity to modify the compound's structure, enhancing its potency and other desirable properties. This will be achieved in an iterative manner by evaluating SF1 and its derivatives physicochemical and antifungal proprieties. 4) To show SF1 safety profile and promising in vivo activity. We will reinforce our preliminary in vitro toxicity analyses (Fig. 4) using the zebrafish embryotoxicity model. A zebrafish model of disseminated candidiasis will also be used to evaluate the in vivo efficacy of SF1. Moreover, we will assess several SF1 and SF1-derivatives physicochemical properties that will provide valuable insights into their potential behavior in vivo. 5) To obtain initial insights into the mechanism of action of SF1. We will employ chemical genomics as a first approach to elucidate the molecular mechanisms underlying SF1 antifungal activity. The goal is to uncover new genes and/or pathways involved in fungal growth and survival in the presence of SF1. This will lay the groundwork for future studies aimed at deepening our understanding of the mechanism of action of SF1, ultimately leading to the design of even more potent SF1 derivatives.