Weill Medical College of Cornell University

• Home
• Overview
• Education
• Fellowships
• Research
• Faculty

Antibiotic Development and Drug Resistance:

Biochemical Approaches to Drug Target Identification. Rhee. A defining interest of our laboratory is the identification and validation of new antibiotic targets. Unlike the case for virtually every other field of medicine, infectious diseases is the only discipline to become progressively less and less effective over time. In large part, this is due to the fact that bacteria replicate far faster and more abundantly than the hosts they infect. As a result, resistance has become the inevitable fate of every antibiotic ever developed. 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.

• de Carvalho LPS, Fischer SM, Marrero J, Nathan C, Ehrt S, Rhee KY. Metabolomics of Mycobacterium tuberculosis reveals compartmentalized co-catabolism of carbon substrates. Chem Biol 2010;17:1122-31.
• de Carvalho LPS, Zhao H, Dickinson CE, Arango N, Lima CD, Fischer S, Ouerfelli O, Nathan C, Rhee KY. Activity-based metabolomic profiling of enzymatic function: identification of Rv1248c as a mycobacterial 2-hydroxy-3-oxoadipate synthase. Chem Biol 2010;17:323-332. *feature article.
• Lakshmanan V, Rhee KY, Wang W, Yu Y, Khafizov K, Fiser A, Wu P, Ndir O, Mboup S, Ndiaye D, Daily J. Metabolomic analysis of patient plasma yields evidence of plant-like α-linolenic acid metabolism in Plasmodium falciparum. J Infect Dis. 2012;206(2):238-48.
• Marrero J, Rhee KY, Pethe K, Schnappiner D, Ehrt S. Gluconeogenic carbon flow of TCA cycle intermediates is critical for Mycobacterium tuberculosis to establish and maintain infection. Proc Natl Acad Sci, U.S.A. 2010;107:9819-24.
• Rhee KY, de Carvalho LPS, Bryk R, Ehrt S, Marrero J, Park S-W, Schnappiner D, Venugopal A, Nathan C. Central carbon metabolism in Mycobacterium tuberculosis: an unexpected frontier. Trends Microbiol. 2011;19:307-14.
• Venugopal A, Bryk R, Shi S, Rhee K, et al. Virulence of Mycobacterium tuberculosis depends on lipoamide dehydrogenase, a member of three multi-enzyme complexes, Cell: Host & Microbe 2011;9:21-31.
• 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.