Biochemical Approaches to Drug Target Identification
A defining interest of our laboratory is the identification of new antibiotic targets and mechanisms. Unlike virtually every other field of medicine, infectious disease is the only discipline to become progressively less and less effective over time. In large part, this is due to the fact that resistance is the inevitable fate of all antibiotics. This problem has been further compounded by the fact that no new mechanistic classes of antibiotics have emerged in the last 40 years. While the reasons for this are multifactorial, it is a commonly overlooked fact that virtually all antibiotics in clinical use were discovered with little foresight and often serendipitously. As a result, we lack sufficient knowledge of what defines a good drug target and how to develop new antibiotics from it. We aim to address this deficiency by applying novel mass spectrometry-based metabolomics approaches to gain insight into the underlying biology of the microbes we wish to target, and their responses perturbation at the pharmacologically relevant level of metabolites. Current efforts focus chiefly on Mycobacterium tuberculosis, Staphylococcus aureus and Enterococcus faecium.
- Wei JR, Krishnamoorthy V, Murphy KC, Kim J-H, Schnappinger D, Alber T, Sassetti CM, Rhee KY, Rubin EJ. Antibiotic targets vary in their sensitivity to inhibition by depletion. Proc Natl Acad Sci, USA. 2011;108:4176-81.
- Chakraborty S, Gruber T, Barry CE, Boshoff HI, Rhee KY. Para-aminosalicylic acid acts as an alternative substrate of folate metabolism in Mycobacterium tuberculosis. Science. 2013;339:88-91.
- Eoh H and Rhee KY. Multifunctional essentiality of succinate metabolism in adaptation to hypoxia in Mycobacterium tuberculosis. Proc Natl Acad Sci USA. 2013;110:6554-59.
- Eoh H, Rhee KY. Methycitrate cycle defines the bactericidal essentiality of isocitrate lyase for survival of Mycobacterium tuberculosis on fatty acids. Proc Natl Acad Sci USA (2014) 111:4976-81.
- Nandakumar M, Nathan C, Rhee KY. (2014) Isocitrate lyase mediates broad antibiotic tolerance in Mycobacterium tuberculosis. Nature Communications. 2014 Jun 30;5:4306.