Margaret A. Phillips
The University of Texas Southwestern Medical Center
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Primary Section: 61, Animal, Nutritional, and Applied Microbial Sciences Secondary Section: 44, Microbial Biology Membership Type:
Member
(elected 2021)
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Biosketch
Margaret (Meg) Phillips is a parasitologist recognized for her work on the biochemistry of protozoan parasites. She is known particularly for her efforts to exploit the pyrimidine biosynthetic pathway in the malaria parasite for drug discovery, and for her identification of an inhibitor of dihydroorotate dehydrogenase that reached clinical development for the treatment of malaria. Phillips was born in Cleveland, Ohio and grew up in San Rafael, California. She graduated from the University of California, Davis with a B.S. in Biochemistry in 1981, and with a Ph.D. in Pharmaceutical Chemistry in 1988 from the University of California, San Francisco, where she was also a postdoctoral fellow in the Department of Biochemistry. She joined the faculty at UT Southwestern in the Department of Pharmacology in 1992, becoming Chair of the Department of Biochemistry in 2016. She is a member of the National Academy of Sciences.
Research Interests
The Phillips lab is interested in the biochemistry of the protozoan pathogens that cause malaria and African sleeping sickness, and on exploiting metabolic vulnerabilities for drug discovery. Her lab has focused on two main areas: 1) targeting the pyrimidine biosynthetic pathway for the treatment of malaria, and 2) studying polyamine metabolism and its regulation in Trypanosoma brucei (causative agent of sleeping sickness). In her malaria program, Phillips employed a high-throughput screen against malaria dihydroorotate dehydrogenase to identify potent and selective inhibitors of the enzyme. Subsequent structure-based lead optimization efforts by her lab and her collaborators lead to the identification of DSM265, which reached clinical development for treatment of malaria. In her trypanosome project, her lab characterized the polyamine biosynthetic pathway, where they explored the fundamental roles of the polyamine biosynthetic enzymes in the parasite, demonstrating that all enzymes in the pathway are essential. They uncovered novel regulatory mechanisms for two enzymes in the pathway, S-adenosylmethionine decarboxylase and deoxyhypusine synthase. Her lab showed that both enzymes require oligomerization with inactive paralogs (i.e., pseudoenzymes) for activity, revealing a trypanosomatid-specific form of enzyme regulation. Subsequent structural studies by her group identified the mechanism of pseudoenzyme activation for both enzymes.
