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Tuberculosis

TB Drug Development

Rhee, Somersan, Isa

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. The reasons for this are multifactorial. However, 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, but have also included studies of Staphylococcus aureus and Enterococcus faecium.

  • 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.
  • Gold B, Pingle M, Brickner SJ, Shah N, Roberts J, Rundell M, Bracken WC, Warrier T, Somersan S, Venugopal A, Darby C, Jiang X, Warren JD, Fernandez J, Ouerfelli O, Nuermberger EL, Cunningham-Bussel A, Rath P, Chidawanyika T, Deng H, Realubit R, Glickman JF, Nathan CF. Nonsteroidal anti-inflammatory drug sensitizes Mycobacterium tuberculosis to endogenous and exogenous antimicrobials. Proc Natl Acad Sci USA 2012;109:16004-11.
  • Nandakumar M, Nathan C, Rhee KY. Isocitrate lyase mediates broad antibiotic tolerance in Mycobacterium tuberculosis. Nature Communications. 2014; 5:4306
  • 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.

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Roy M. Gulick, M.D., Chief

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