The Role of the Glyoxylate Cycle in the Pathogenesis of Mycobacterium tuberculosis

<p>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 icl1 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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Thesis

Year

2005

Author dc:creator

• Muñoz Elías, Ernesto Javier

Contributors dc:contributor

• John McKinney

• Mycobacterium tuberculosis
• glyoxylate cycle
• methylcitrate cycle
• isocitrate lyase
• tuberculosis drug development
• Life Sciences

Repository record dc:identifier

https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/55

OAI identifier oai:identifier

oai:digitalcommons.rockefeller.edu:student_theses_and_dissertations-1054