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Tuberculosis

TB Drug Development

Rhee

A defining interest of our laboratory is the identification of new antibiotic targets and mechanisms. Unlike virtually every other field of medicine, infectious diseases has become progressively less and less effective over time. The reasons for this are multifactorial. However, a commonly overlooked fact is that virtually all antibiotics in clinical use were discovered serendipitously with little foresight. 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 Mycobacterium tuberculosis (ie, what makes TB TB) and its response to perturbation at the pharmacologically relevant level of metabolites. While current efforts focus chiefly on Mycobacterium tuberculosis, previous work has included studies of Staphylococcus aureus and Enterococcus faecium.

Ehrt S, Schnappinger D, Rhee KY. Metabolic principles of persistence and pathogenicity in Mycobacterium tuberculosis. Nat Rev Microbiol. 2018 Aug;16(8):496-507.

Jansen RS, Mandyoli L, Hughes R, Wakabayashi S, Pinkham JT, Selbach B, Guinn KM, Rubin EJ, Sacchettini JC, Rhee KY. Aspartate aminotransferase Rv3722c governs aspartate-dependent nitrogen metabolism in Mycobacterium tuberculosis. Nat Commun. 2020 Apr 23;11(1):1960.

Wang Z, Soni V, Marriner G, Kaneko T, Boshoff HIM, Barry CE 3rd, Rhee KY. Mode-of-action profiling reveals glutamine synthetase as a collateral metabolic vulnerability of M. tuberculosis to bedaquiline. Proc Natl Acad Sci U S A. 2019 Sep 24;116(39):19646-19651.

Ballinger E, Mosior J, Hartman T, Burns-Huang K, Gold B, Morris R, Goullieux L, Blanc I, Vaubourgeix J, Lagrange S, Fraisse L, Sans S, Couturier C, Bacqué E, Rhee K, Scarry SM, Aubé J, Yang G, Ouerfelli O, Schnappinger D, Ioerger TR, Engelhart CA, McConnell JA, McAulay K, Fay A, Roubert C, Sacchettini J, Nathan C. Opposing reactions in coenzyme A metabolism sensitize Mycobacterium tuberculosis to enzyme inhibition. Science. 2019 Feb 1;363(6426):eaau8959.

Isa F, Collins S, Lee MH, Decome D, Dorvil N, Joseph P, Smith L, Salerno S, Wells MT, Fischer S, Bean JM, Pape JW, Johnson WD, Fitzgerald DW, Rhee KY. Mass Spectrometric Identification of Urinary Biomarkers of Pulmonary Tuberculosis. EBioMedicine. 2018 May;31:157-165.

Eoh H, Wang Z, Layre E, Rath P, Morris R, Branch Moody D, Rhee KY. Metabolic anticipation in Mycobacterium tuberculosis. Nat Microbiol. 2017 May 22;2:17084.

Jansen RS, Rhee KY. Emerging Approaches to Tuberculosis Drug Development: At Home in the Metabolome. Trends Pharmacol Sci. 2017 Apr;38(4):393-405.