PgmNr Y3162: Identifying novel small molecules for improved antifungal drug treatment.

Authors:
Kevin F. Murphy ¹ ; Dina Wassaf ² ; Angela N. Koehler ³ ; Martha L. Bulyk ^4,5

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Institutes
1) Department of Biology and Health Sciences, McNeese State University, Lake Charles, LA; 2) Broad Institute, Cambridge, MA; 3) Koch Institute for Integrated Cancer Research at MIT, Cambridge, MA; 4) Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; 5) Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

Keyword: Human diseases/Drug Discovery

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Abstract:

Invasive fungal infections (IFIs) are associated with high rates of morbidity and mortality and pose a serious health concern for severely immunocompromised patients. Fungal resistance to current drug therapies is largely due to the transcriptional upregulation of membrane associated efflux pumps, which expel from the cell a myriad of structurally diverse molecules, including antifungal drugs, thus severely reducing their effectiveness against these pathogens.  Additionally, resistance can arise by overexpression of drug target genes within the ergosterol biosynthesis pathway. The fungal-specific zinc cluster (Zn₂Cys₆) family of transcription factors (TFs) is primarily responsible for the upregulation of these efflux pumps and ergosterol biosynthesis enzymes and thereby mediating pleiotropic drug resistance (PDR) in yeast. Thus, these TFs offer an attractive and rational target for the development of new antifungal drugs.

In pursuit of this goal, we aimed to identify small molecules capable of inhibiting the DNA-binding ability of Zn₂Cys₆ TFs regulating PDR in yeast. An initial screen utilizing small molecule microarrays (SMM) was employed to identify compounds capable of binding the DNA-binding domain of Zn₂Cys₆ TF Pdr1p from Candida glabrata.  In our initial SMM-based screen, a library of 15,000 different compounds was examined and yielded 76 unique compounds that specifically bound to Pdr1p.  Small-molecule “hit” compounds consisted of several different structural classes, including 44 azetidine and sulfonamide-based compounds. Future studies will examine the potential of these lead compounds for development of improved antifungal drugs in the treatment of IFIs.