New Antifungal Agents as Topical and Systemic Therapies for Wound and Invasive Infections
Abstract
This proposal is directed at the development of a novel antifungal agent that can be administered topically and/or systemically to treat life-threatening infections at surgical or trauma-induced wounds. The identification and evaluation of novel and/or innovative antifungals against fungal infections, particularly for use as topical therapies for wounds, was explicitly described as an Area of Encouragement under the Antimicrobial Resistance Topic Area. If not treated effectively, wound infections can spread through the body causing so-called invasive fungal infections (IFIs) that frequently result in death of the patient. IFIs can also occur in patients afflicted with HIV or undergoing cancer therapies who have severely depressed immune systems and can no longer fight invading microbes. IFIs can also occur in normal immune systems and the most common cause is from skin and soft tissue wounds resulting from traumatic injury, such as blast or other severe wounds inflicted on Soldiers in the battlefield. In both immunosuppressed and immunocompetent patients, the most common fungal pathogens are Candida, Aspergillus, Cryptococcus, Mucorales, and Fusarium. Infections caused by these pathogens are associated with a high number of treatment failures and high death rates, reaching 30% to 50% in many cases. In the military, major advances in combat casualty care have resulted in increased survival rates for Soldiers with complex extremity injuries and IFIs have become an emerging trauma-related infection that leads to significant complications. Blast traumas are among the most severe injuries and wounds can be contaminated by soil material containing numerous types of fungal pathogens. The local invasive infections in these instances often require frequent and extensive surgical procedures in conjunction with systemic antifungal therapies but even so amputations have been reported to be needed in 31% of cases and death rates were as high as 25%. The most common antifungal agents used to treat IFIs are the polyenes, azoles, and echinocandins. Despite recent advances in treatment and diagnosis, the incidence of IFIs continues to rise and several important medical needs persist for their prevention and treatment: (1) perhaps most significantly, death rates remain high; (2) treatment times are long, extending to weeks and months, which increases the potential for resistance development caused by poor patient compliance and inadequate drug effectiveness; (3) emerging drug-resistant pathogens such as Candida auris and Scedosporium are becoming a serious medical threat; (4) resistance is building to the current antifungals, especially for the azoles and echinocandins, and (5) safety is an issue since many patients have a compromised health status. The high treatment failure rates in both immunosuppressed and immunocompetent patients coupled with the present day medical needs summarized above clearly underscore the urgent need for new antifungal agents that can be used to treat a broad range of fungal infections and possibly synergize with existing antifungals to more effectively control these life-threatening infections. We have developed a series of novel compounds that mimic antimicrobial proteins that make up part of our own innate immune system that act to prevent local infections. Several compound series were optimized to enhance antifungal activity and we have continued chemical optimization to broaden the spectrum of activity against fungal pathogens and improve safety. This has led to the identification of several lead compounds that display potent killing activities against numerous fungi that cause human infections and are active in animal models of topical and disseminated infections. The activity profiles of these lead compounds provide a promising foundation for the development of new and effective antifungal agents that act differently from existing antifungals. In accordance with the program announcement, the primary foc
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810638
Entities
People
- Richard Scott
Organizations
- Fox Chase Chemical Diversity Center
- United States Army