(796.18) Targeting Pantothenate Kinase as an Effective Strategy for Antifungal Drug Development

Poster Board Number: A169

Shalev Gihaz (Yale University School of Medicine), Peter Gareiss (Yale Center for Molecular Discovery), Jae-Yeon Choi (Yale University School of Medicine), Isaline Renard (Yale University School of Medicine), Anasuya Chattopadhyay Pal (Yale University School of Medicine), Yulia Surovsteva (Yale Center for Molecular Discovery), Joy Chiu (Yale University School of Medicine), Jose Thekkiniath (Yale University School of Medicine), Mark Plummer (Yale Center for Molecular Discovery), William Hungerford (Yale Center for Molecular Discovery), Micaela Montgomery (University of Oklahoma Health Sciences Center- Department of Microbiology and Immunology), Alanah Hosford (University of Oklahoma Health Sciences Center- Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center- Department of Microbiology and Immunology), Emily Adams (University of Oklahoma Health Sciences Center- Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center- Department of Microbiology and Immunology), Jorge Lightfoot (University of Oklahoma Health Sciences Center- Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center- Department of Microbiology and Immunology), David Fox III (Seattle Structural Genomics Center for Infectious Disease, Seattle Structural Genomics Center for Infectious Disease, Seattle Structural Genomics Center for Infectious Disease), Kayode Ojo (University of Washington), Bart Staker (Seattle Structural Genomics Center for Infectious Disease, Seattle Structural Genomics Center for Infectious Disease), Kevin Fuller (University of Oklahoma Health Sciences Center- Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center- Department of Microbiology and Immunology), Choukri Ben Mamoun (Yale University School of Medicine)

Fungal infections affect over one billion people worldwide each year and are the leading cause of mortality by eukaryotic pathogens with an estimated 150 million severe life-threatening cases and 1.7 million deaths reported annually. The rapid increase in the number of clinical cases and the emergence of multidrug resistant pathogens such as Candida auris emphasize the urgent need for new strategies to develop more effective, selective and safe antifungals. Coenzyme A (CoA) plays a central role in key cellular processes including the citric acid cycle, lipid metabolism, and ergosterol biosynthesis. The first step in the CoA biosynthesis pathway is catalyzed by a pantothenate kinase (PanK), which phosphorylates pantothenic acid (PA, or vitamin B5) to form phosphopantothenate. In fungi, this enzyme is encoded by a single copy PanK gene, which plays an essential role in cell viability. Here, we report the first crystal structure of the S. cerevisiae PanK enzyme, Cab1, at 1.8Å resolution. Cab1 was crystallized alone and in the presence of three lead high-affinity inhibitors identified in a high-throughput chemical screen of a library of 156,593 small molecules. Structure-guided mutagenesis together with functional complementation assays in yeast identified key residues in Cab1 that are essential for catalysis, substrate binding and dimerization. Structure activity relationship and biological assays identified a lead inhibitor YU385599, with excellent activity against the human pathogens Candida albicans, C. glabrata, and C. parapsilosis. Together, our data validate PanK activity as a novel drug target and identify a novel class of small molecules for the treatment of fungal diseases.

This research was supported by funds from NIH, Cohen Foundation, Global Lyme Alliance
and the Blavatnik Fund. This project has also been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN272201700059C.