Antifungal therapy against drug resistant fungal pathogens.

DESCRIPTION provided by applicant Despite medical advances fungal infections still exact a heavy burden on the HIV AIDs population AIDs related fungal infections account for of all AIDs related deaths In the developed world AIDS related fungal infections are most frequently associated with Candida albicans but Aspergillus fumigatus and Cryptococcus neoformans are also common Unfortunately the number of treatments for invasive fungal infections has remained relatively stagnant Also the three most widely used classes of antifungals collectively inhibit only a few molecular targets As a consequence of their widespread use an increasing numbers of invasive fungi are resistant to multiple antifungals A promising new strategy to enhance the efficacy of antifungals and block the evolution of drug resistance is to inhibit the molecular chaperone heat shock protein Hsp Hsp an essential molecular chaperone regulates the stability of its client proteins many of which are involved in stress responses Fungi depend on these stress responses to cope with cell membrane and cell wall damage induced by antifungal drugs Inhibiting Hsp would dismantle cellular stress response circuitry and thus abrogate drug resistance and dramatically enhance the efficacy of antifungal medications Previous research has demonstrated that an Hsp inhibitor abolished drug resistance in azole resistant and echinocandin resistant strains Hsp inhibition also impairs the acquisition of resistance When Hsp is depleted or inhibited in the yeast model organism Saccharomyces cerevisiae or in C albicans the evolution of resistance to azoles is impaired While several Hsp inhibitors are in development for cancer treatment these inhibitors work on both fungal and human Hsp thereby making them toxic as antifungals Our compound LP could be an important advancement in treating fungal infections To our knowledge LP is the first characterized small molecule that selectively inhibits fungal Hsp It works in combination with known antifungals against a broad range of pathogenic fungi It is a novel patentable easily analoged and small molecular weight compound that demonstrates a promising safety profile Our overarching research plan is to advance LP and or its analogs as a pre clinical candidate We will synthesize LP perform complete ADME experiments to determine its likely pharmacokinetic properties measure its ability to retard fungal biofilm and determine the efficacy and safety of LP in five in vivo mouse models We will develop resistant strains of C albicans to help define LP s mechanism of action Even though LP has impressive activity and specificity in our assays we will also synthesize analogs of LP because they may have better in vivo properties We will investigate these analogues in a manner similar to the above mentioned process for LP To accomplish these goals we have assembled an excellent team including Timo Ovaska Professor of Chemistry at Connecticut College Mahmoud A Ghannoum Director of The Center for Medical Mycology at Case Western Reserve University and Leah Cowen Assistant Professor at the University of Toronto PUBLIC HEALTH RELEVANCE Fungal infections continue to be a major cause of morbidity and mortality among HIV infected patients There have been an increased number of varied and resistant fungal pathogens that are difficult to treat Also there are very few fungal specific targets that are appropriate for drug discovery A promising new strategy to enhance the efficacy of antifungals and block the evolution of drug resistance is to inhibit the molecular chaperone heat shock protein Hsp Hsp an essential molecular chaperone regulates the stability of its client proteins many of which are involved in stress responses Fungi depend on these stress responses to cope with cell membrane and cell wall damage induced by antifungal drugs Our compound could be an important advancement in treating fungal infections To our knowledge it is the first characterized small molecule that selectively inhibit fungal Hsp It works in combination with known antifungals against a broad range of pathogenic fungi We intend to use this SBIRII to develop this compound and its analogs as a novel treatment for fungal infections