New Strategies to Detect and Prevent Tuberculosis
2008-12 Seed Grant
This program aims to discover and implement novel strategies for the detection and prevention of tuberculosis in humans. Because pre-clinical evaluation of anti-tuberculosis regimens in animal models is resource and time intensive, the goal is to use imaging technologies to monitor surrogate markers of response to anti-tuberculosis therapy.
The basic premise is that detection of siderophore production by Myobacterium tuberculosis can be exploited as an early indication of infection. Groves and Rabinowitz aim to apply high-level mass spectrometric techniques to monitor changes in metabolite profiles within human cells upon exposure to such siderophores.
One important result has been the design and successful completion of a novel and efficient total synthesis of the siderophore mycobactin T.
This important bacterial metabolite, for which there is no other source, was required for the rest of the project. This research team has also completed a study of the effects of siderophores on human and mouse cells, and supplies of mycobactin T have been provided to collaborators at Johns Hopkins for studies with the live human pathogen.
A component on molecular aspects of modern drug design has been added to "Advanced Organic Chemistry," which was co-taught by Erik Sorensen and Jay Groves. Three undergraduate theses have been supported by this work, including one by James Yan (P ’09) that elucidated an import aspect of the host-pathogen interaction – where does the iron needed by the pathogen originate in the host and how does the pathogen secure that iron? Graduate student Kiat-Hwa Chan, who successfully completed a laboratory synthesis of the tuberculosis siderophore mycobactin-T, defended his Ph.D. thesis in October of 2010. Graduate student Courtney McQueen, who studied iron acquisition by mycobactin, completed her Ph.D. thesis in June of 2010.
Courtney McQueen and John Groves both gave invited oral presentations on the project at the national meeting of the American Chemical Society in Philadelphia in August 2008.
The team plans to validate high resolution computed tomography (CT) as a surrogate marker for real-time evaluation of response to anti-TB therapy in the mouse and guinea pig models. They also plan to develop novel single photon emission computed tomography (SPECT) for real-time evaluation of Mycobacterium tuberculosis (Mtb) bacterial burden in the mouse and guinea pig models of TB, in collaboration with the Johns Hopkins group. Finally they will synthesize radio-labeled 67Ga-mycobactin-T for use with SPECT, capable of real-time evaluation of Mtb burden in human disease.