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Mycobacterium tuberculosis isocitrate lyases 1 and 2 are jointly required for in vivo growth and virulence

Nature Medicine volume 11, pages 638–644 (2005)Cite this article

Abstract

Genes involved in fatty acid catabolism have undergone extensive duplication in the genus Mycobacterium, which includes the etiologic agents of leprosy and tuberculosis. Here, we show that prokaryotic- and eukaryotic-like isoforms of the glyoxylate cycle enzyme isocitrate lyase (ICL) are jointly required for fatty acid catabolism and virulence in Mycobacterium tuberculosis. Although deletion of icl1 or icl2, the genes that encode ICL1 and ICL2, respectively, had little effect on bacterial growth in macrophages and mice, deletion of both genes resulted in complete impairment of intracellular replication and rapid elimination from the lungs. The feasibility of targeting ICL1 and ICL2 for chemical inhibition was shown using a dual-specific ICL inhibitor, which blocked growth of M. tuberculosis on fatty acids and in macrophages. The absence of ICL orthologs in mammals should facilitate the development of glyoxylate cycle inhibitors as new drugs for the treatment of tuberculosis.

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Figure 1: Glyoxylate cycle and related metabolic pathways in M. tuberculosis.
Figure 2: Overlapping roles of ICL1 and ICL2 in fatty acid catabolism.
Figure 3: Virulence of ICL-deficient M. tuberculosis in mice.
Figure 4: Survival of ICL-deficient M. tuberculosis in macrophages.
Figure 5: Chemical inhibition of ICL blocks growth of M. tuberculosis on fatty acids.
Figure 6: Chemical inhibition of ICL blocks M. tuberculosis growth in macrophages.

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Acknowledgements

We thank N. Mirkovic and A. Sâli for construction of the ICL2 in silico model, B. Hanna for use of the BACTEC apparatus, J. Timm for assistance with real-time RT-PCR assays, M. Glickman for providing the cosmid containing icl2, S. Ehrt for providing the L-cell line and W.T. Chan and P. Giannakas for technical assistance. E.J.M.-E was supported by a Robert D. Watkins Graduate Fellowship from the American Society for Microbiology. J.D.M. acknowledges support from the Sequella Global Tuberculosis Foundation, the Ellison Medical Foundation, the Sinsheimer Fund and the Irma T. Hirschl Trust. This work was funded by grants (to J.D.M.) from GlaxoSmithKline and the US National Institutes of Health (AI46392).

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  1. Laboratory of Infection Biology, The Rockefeller University, 1230 York Avenue, New York, 10021, New York, USA

    Ernesto J Muñoz-Elías & John D McKinney

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Correspondence to John D McKinney.

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Supplementary Table 1

Enzymes, genes and genome designations. (PDF 207 kb)

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Muñoz-Elías, E., McKinney, J. Mycobacterium tuberculosis isocitrate lyases 1 and 2 are jointly required for in vivo growth and virulence. Nat Med 11, 638–644 (2005). https://doi.org/10.1038/nm1252

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