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Journal of Bacteriology, August 2009, p. 5037-5043, Vol. 191, No. 16
0021-9193/09/$08.00+0     doi:10.1128/JB.00530-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Triacylglycerol Utilization Is Required for Regrowth of In Vitro Hypoxic Nonreplicating Mycobacterium bovis Bacillus Calmette-Guerin{triangledown}

Kai Leng Low,1 P. S. Srinivasa Rao,4* Guanghou Shui,2 Anne K. Bendt,2 Kevin Pethe,4 Thomas Dick,4 and Markus R. Wenk1,2,3*

NUS Graduate School for Integrative Sciences and Engineering (NGS),1 Department of Biochemistry, Yong Loo Lin School of Medicine,2 Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore 117456, Republic of Singapore,3 Tuberculosis Unit, Novartis Institute for Tropical Diseases (NITD) Pte. Ltd., Singapore 138670, Republic of Singapore4

Received 21 April 2009/ Accepted 2 June 2009

Mycobacteria store triacylglycerols (TGs) under various stress conditions, such as hypoxia, exposure to nitric oxide, and acidic environments. These stress conditions are known to induce nonreplicating persistence in mycobacteria. The importance of TG accumulation and utilization during regrowth is not clearly understood. Here we specifically determined the levels of accumulated TG and TG lipase activity in Mycobacterium bovis bacillus Calmette-Guerin (BCG) in various different physiological states (logarithmic growth, aerated stationary phase, hypoxia-induced dormancy, and regrowth from dormancy). We found extensive accumulation and degradation of TGs in the bacilli during entry into and exit from hypoxia-induced dormancy, respectively. These processes are accompanied by dynamic appearance and disappearance of intracellular TG lipid particles. The reduction in TG levels coincides with an increase in cellular TG lipase activity in the regrowing bacilli. Tetrahydrolipstatin, an inhibitor of TG lipases, reduces total lipase activity, prevents breakdown of TGs, and blocks the growth of mycobacteria upon resuscitation with air. Our results demonstrate that utilization of TGs is essential for the regrowth of mycobacteria during their exit from the hypoxic nonreplicating state.

* Corresponding author. Mailing address for P. S. Srinivasa Rao: 10 Biopolis Road, Chromos Building, Level 05-01, Singapore 138670, Republic of Singapore. Phone: (65) 67222944. Fax: (65) 67222917. E-mail: srinivasa.rao{at}novartis.com. Mailing address for Markus R. Wenk: 28 Medical Drive, Level 04-21, Singapore 117456, Republic of Singapore. Phone: (65) 65163624. Fax: (65) 67773271. E-mail: bchmrw{at}nus.edu.sg

{triangledown} Published ahead of print on 12 June 2009.

Journal of Bacteriology, August 2009, p. 5037-5043, Vol. 191, No. 16
0021-9193/09/$08.00+0     doi:10.1128/JB.00530-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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