Oral infections by Candida albicans represent an increasing problem in human health. In immunocompromised individuals, especially those suffering from AIDS, candidiasis can result in both localized, yet painful lesions in the oral cavity as well as life-threatening systemic infections. Systemic infections are extremely severe, and while numerous antifungals are used in treatment, mortality still remains high, ranging from 15-40% for adults and 19-31% for neonates and children. Furthermore, due to the use of standard antifungal treatments, an increasing number of infections are due to non-albicans Candida (NAC) and drug-resistant species. Infection by Candida has now become the fourth most common nosocomial infection in the blood in the US. Therefore, it is critically important to develop new therapeutic agents that exhibit potent activity against all Candida species, with a mechanism of action that does not lead to the rapid development of resistance.
We have identified a series defensin-mimetic compounds that are highly active against Candida species and exhibit very low cytotoxicity against mammalian cell types. Laboratory experiments have shown that, like the anti-bacterial defensin-mimetics, the potential for resistance development by Candida is very low. One of our early lead compounds,, CTIX-1502, was tested in 2 models of oral candidiasis in mice with an active or disabled immune system. In both cases, following a single topical administration, CTIX-1502 caused a significant reduction in the number of viable Candida that was comparable or superior to the commonly used topical anti-fungal agent, Nystatin. CTIX-1502 was also tested in mouse models of systemic Candida infection. The defensin-mimetic showed robust killing activity of Candida in infected tissues and prevented mortality at levels superior to other widely used anti-fungal agents. This important proof-of-concept data substantiates our approach to develop novel therapies against fungal infections, an indication of utmost clinical need where substantial mortality is encountered with available anti-fungal medications.
