Mycobacterial Pathogenesis and Novel Therapeutic Targets

 Laurent KREMER

IRIM - UMR 9004

1919, route de Mende, 34293 Montpellier

Phone: +33 4 34 35 94 47

Email: laurent.kremer@irim.cnrs.fr

Website

We explore the cell envelope of pathogenic mycobacteria in the interactions with the host (i) to better understand how Mycobacterium tuberculosis and Mycobacterium abscessus highjack the host immune response; (ii) to describe the physiopathology of the associated diseases, and (iii) to dissect drug resistance mechanisms and identify new therapeutic targets for future pharmacological developments. We are focusing our work on major cell wall components, including mycolic acids or glycopeptidolipids, with respect to their biosynthesis, regulation and roles in mycobacterial biology and pathogenicity. Special attention is also given on host-pathogen interactions using macrophages as well as the Mycobacterium marinum/zebrafish model of infection that allow to investigate the early events of infections and the role of innate immunity in controlling bacterial growth/survival. We are particularly concentrating our efforts on elucidating the mechanisms of internalization of host cells by pathogenic mycobacteria and on the contribution of tetraspanins in the invasion event.

Keywords: Mycobacterium, tuberculosis, cell wall, biosynthesis, drug target, zebrafish, innate immunity

Main publications

• A. Viljoen, M. Richard, P. C. Nguyen, P. Fourquet, L. Camoin, R. R. Paudal, G. R. Gnawali, C. D. Spilling, J. F. Cavalier, S. Canaan, M. Blaise, and L. Kremer. 2018. Cyclipostins and cyclophostin analogs inhibit the antigen 85C from Mycobacterium tuberculosis both in vitro and in vivo. J. Biol. Chem. 293: 2755–2769.
• A. Bernut, M. Nguyen-Chi, I. Halloum, J.L. Herrmann, G. Lutfalla, and L. Kremer. 2016. Mycobacterium abscessus-induced granuloma formation is strictly dependent on TNF signaling and neutrophil trafficking. PLOS Pathog. 12: e1005986.
• Halloum S., Carrère-Kremer S., M. Blaise A., Viljoen A., Bernut A., Le Moigne V., Vilchèze C., Guérardel Y., Lutfalla G., Herrmann J.L., Jacobs W.R., Jr., and Kremer L. (2016) Deletion of a dehydratase important for intracellular growth and cording renders rough Mycobacterium abscessus avirulent.  Proc. Natl. Acad. Sci USA. 113: E4228-4237.
• A. Viljoen, M. Blaise, C. de Chastellier, and L. Kremer. 2016. MAB_3551c encodes the primary triacylglycerol synthase involved in lipid accumulation in Mycobacterium abscessus. Mol Microbiol. 102: 611-627.
• Dupont C., Viljoen A., Dubar F., Blaise M., Bernut A., Pawlik A., Bouchier C., Brosch R., Guérardel Y., Lelièvre J., Ballell L., Herrmann J.L., Biot C., and Kremer L. (2016) A new piperidinol derivative targeting mycolic acid transport in Mycobacterium abscessus. Mol. Microbiol. 101: 515-529.
• Singh V., Berry L., Bernut A., Singh S., Carrère-Kremer S., Viljoen A., Alibaud L., Majlessi L., Brosch R., Chaturvedi V., Geurtsen J., Drancourt M., and Kremer L. (2016) A unique PE_PGRS protein inhibiting host cell cytosolic defenses and sustaining full virulence of Mycobacterium marinum in multiple hosts. Cell. Microbiol. 18: 1489-1507.
• Bernut A., Viljoen A., Dupont C., Sapriel G., Blaise M., Bouchier C., Brosch R., de Chastellier C., Herrmann J.L., and Kremer L. (2016) Insights into the smooth-to-rough transitioning in Mycobacterium bolletii unravels a functional Tyr residue conserved in all mycobacterial MmpL family members. Mol. Microbiol. 99: 866-83.
• Carrère-Kremer S., Blaise M., Singh V.K., Alibaud L., Tuaillon E., Halloum I., van de Weerd R., Guérardel Y., Drancourt M., Takiff H., Geurtsen J., and Kremer L. (2015) A new dehydratase conferring innate resistance to thiacetazone and intra-amoebal survival of Mycobacterium smegmatis. Mol. Microbiol. 96: 185-1102.
• Vilchèze C., Molle V., Carrère-Kremer S., Leiba J., Mourey L., Shenai S., Baronian G., Tufariello J., Hartman T., Veyron-Churlet R., Trivelli X., Tiwari S., Weinrick B., Alland D., Guérardel Y., Jacobs W.R., Jr., and Kremer L. (2014) Phosphorylation of KasB regulates virulence and acid-fastness in Mycobacterium tuberculosis. PLOS Pathog. 10: e1004115.
• Bernut A., Herrmann J.L., Kissa K., Dubremetz J.F, Gaillard J.L., Lutfalla G., and Kremer L. (2014) Mycobacterium abscessus cording prevents phagocytosis and promotes abscess formation. Proc. Natl. Acad. Sci USA. 111: E943-952.