Treatment or Prevention of Fungal Infections with PDK1 Inhibitors

Abstract

Provided are methods of treating or preventing a fungal infection in a subject. The methods comprise identifying a subject with or at risk of developing a fungal infection and administering to the subject a therapeutically effective amount of an inhibitor or a fungal phosphoinositide-dependent kinase 1 (PDK-1) or a homolog thereof. Inhibition of the fungal PDK-1 or homolog thereof results in the treatment or prevention of a fungal infection in the subject. Also provided are compositions comprising an inhibitor of a fungal phosphoinositide-dependent kinase 1 (PDK-1) or a homolog thereof, and a pharmaceutically acceptable carrier.

What is claimed is: 
     
         1 . A method of treating or preventing a fungal infection in a subject, the method comprising:
 (a) identifying a subject with or at risk of developing a fungal infection, and   (b) administering to the subject a therapeutically effective amount of an inhibitor of a fungal phosphoinositide-dependent kinase 1 (PDK1) or a homolog thereof, wherein inhibition of the fungal PDK1 or homolog thereof results in the treatment or prevention of the fungal infection in the subject.   
     
     
         2 . The method of  claim 1 , wherein the PDK1 homolog is phosphoinositide-dependent kinase homolog 1 (Pkh1). 
     
     
         3 . The method of  claim 1 , wherein the PDK1 homolog is phosphoinositide-dependent kinase homolog 2 (Pkh2). 
     
     
         4 . The method of  claim 1 , wherein the fungal infection is caused by a fungus selected from the group consisting of  Candida  spp.,  Cryptococcus  spp.,  Aspergillus  spp.,  Nocardia  spp., or  Saccharomyces  spp. 
     
     
         5 . The method of  claim 4 , wherein the fungal infection is caused by  Candida  spp. 
     
     
         6 . The method of  claim 5 , wherein the  Candida  spp. is selected from the group consisting of  Candida albicans, Candida glabrata, Candida parapsilosis, Candida dubliensis, Candida tropicalis, Candida lusitaniaem, Candida pseudoguillerimondi , and  Candida krusei.   
     
     
         7 . The method of  claim 6 , wherein the fungal infection is caused by  Candida albicans.   
     
     
         8 . The method of  claim 4 , wherein the fungal infection is caused by  Cryptococcus  spp. 
     
     
         9 . The method of  claim 8 , wherein the fungal infection is caused by  Cryptococcus neoformans.   
     
     
         10 . The method of  claim 1 , wherein the subject is administered a therapeutically effective amount of KP-372-1. 
     
     
         11 . The method of  claim 10 , wherein the subject is further administered a therapeutically effective amount of fluconazole. 
     
     
         12 . The method of  claim 10 , wherein the subject is administered a dose of at least 3 mg/kg. 
     
     
         13 . The method of  claim 12 , wherein the subject is administered a dose of 100 mg/kg. 
     
     
         14 . The method of  claim 1 , wherein the subject is administered a therapeutically effective amount of OSU-0312 or a derivative thereof. 
     
     
         15 . The method of  claim 14 , wherein the subject is further administered a therapeutically effective amount of fluconazole. 
     
     
         16 . The method of  claim 14 , wherein the subject is administered a dose of at least 3 mg/kg. 
     
     
         17 . The method of  claim 16 , wherein the subject is administered a dose of 100 mg/kg. 
     
     
         18 . The method of  claim 1 , wherein the inhibitor of fungal PDK1 or a homolog thereof inhibits the expression of fungal PDK1 or the homolog thereof. 
     
     
         19 . A composition comprising an inhibitor of a fungal phosphoinositide-dependent kinase 1 (PDK1) or a homolog thereof, and a pharmaceutically acceptable carrier. 
     
     
         20 . The composition of  claim 19 , wherein the PDK1 homolog is phosphoinositide-dependent kinase homolog 1 (Pkh1). 
     
     
         21 . The composition of  claim 19 , wherein the PDK1 homolog is phosphoinositide-dependent kinase homolog 2 (Pkh2). 
     
     
         22 . The composition of  claim 19 , wherein the inhibitor of PDK1 or a homolog thereof is KP-372-1 or a derivative thereof. 
     
     
         23 . The composition of  claim 22 , wherein the composition further comprises fluconazole. 
     
     
         24 . The composition of  claim 19 , wherein the inhibitor of PDK1 or a homolog thereof is OSU-0312 or a derivative thereof. 
     
     
         25 . The composition of  claim 24 , wherein the composition further comprises fluconazole.