Student Theses and Dissertations
Date of Award
2005
Document Type
Thesis
RU Laboratory
Deans Office
Keywords
mycobacterium tuberculosis, glyoxylate cycle, methyl citrate cycle, isocitrate lyase, m.tuberculosis drug development
Abstract
According to the World Health Organization a third of the world's population is infected with Mycobacterium tuberculosis. The unparalleled success of M. tuberculosis as a pathogen reflects the bacterium's extraordinary ability to persist in its host in spite of eliciting a robust immune response. Currently available treatment is inadequate and drug resistance is rapidly spreading. New antibiotics are desperately needed. The substrates and metabolic pathways utilized by pathogens during infection are largely unknown and represent an under-exploited area of investigation. Uniquely, evolution of the genus Mycobacterium has involved extensive duplication of fatty acid metabolism genes, including two homologs encoding prokaryotic- and eukaryotic-like isoforms of the glyoxylate cycle enzyme isocitrate lyase (ICL). The glyoxylate cycle is employed by cells when fatty acids are the main carbon source available. Here, we show that these enzymes are jointly required by M. tuberculosis for growth on fatty acids and for virulence in experimental infections. Although deletion of icll or icl2 had little impact on replication of M. tuberculosis in macrophages and mice, deletion of both genes abrogated intracellular growth, and resulted in rapid bacterial clearance from the lungs. A dual-specificity ICL inhibitor similarly blocked replication of M. tuberculosis on fatty acids in vitro and in macrophages. The absence of ICL orthologs in mammals, and recent findings implicating the glyoxylate pathway in the virulence of other bacterial and fungal pathogens makes this metabolic pathway an attractive novel target for drug development.
Permanent URL
http://hdl.handle.net/10209/231
Recommended Citation
Munoz-Elias, Ernesto Javier, "The Role of the Glyoxylate Cycle in the Pathogenesis of Mycobacterium tuberculosis" (2005). Student Theses and Dissertations. 55.
https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/55
Comments
A thesis presented to the faculty of The Rockefeller University in partial fulfillment of the requirements for the degree of Doctor of Philosophy.