Fungi cause a wide spectrum of disease states. The most common examples are relatively minor, localized infections of the skin and mucous membranes such as athlete's foot, vaginal yeast infections, and infections of keratinized nails. However, an ominously increasing number of fungi cause systemic disease with the involvement of internal organs. These have become serious and life-threatening problems that are very difficult to diagnose and even more challenging to treat in patients with impaired host-defense mechanisms. ? ? Part of the difficulty in treating fungal infections, especially in immunocompromised hosts, is the limited armamentarium of antifungal drugs. Currently-available drugs include polyenes (e.g., amphotericin B) that complex with fungal-membrane ergosterol, a number of azoles and allylamines that inhibit steps in the ergosterol biosynthetic pathway, flucytosine that inhibits nucleic acid synthesis, and Cancidas, a (1,3)beta-glucan synthase inhibitor. Unfortunately, amphotericin B has a number of acute and chronic adverse effects. Flucytosine has a narrow spectrum of activity and is plagued with treatment failures due to the development of resistant fungi. Azoles are only fungistatic and resistance to commonly-used azoles is becoming a significant clinical problem. There is general agreement that there is a critical and immediate need for novel drugs with mechanisms of action different from current drugs. ? ? The applicant's long-term goal is to discover novel antifungals that are active against enzymes of the glyoxylate cycle. The glyoxylate cycle, which is absent in humans, is essential for fungal pathogenicity and represents an unexploited pathway for the development of antifungal drugs. The investigators will accomplish this in Two Aims: (1) to isolate and identify 5 to10 inhibitors of the glyoxylate cycle enzymes and determine their potency against fungal cells and toxicity against human cells; (2) to determine the in vivo efficacy of two of the most active compounds using a Candida albicans murine model. Ultimately, this work will lead to the isolation of new classes of compounds for treatment of human fungal disease. The applicant predicts that, since humans do not have the glyoxylate cycle, the inhibitors will be safe and effective therapeutics. ? ?
