Journal
MICROBIOLOGY-SGM
Volume 156, Issue -, Pages 81-87Publisher
SOC GENERAL MICROBIOLOGY
DOI: 10.1099/mic.0.033084-0
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The ability of Mycobacterium tuberculosis to persist in its human host despite extensive chemotherapy is thought to be based on subpopulations of non-replicating phenotypically drug-resistant bacilli. To study the non-growing pathogen, culture models that generate quiescent organisms by either oxygen depletion in nutrient-rich medium (Wayne model) or nutrient deprivation in oxygen-rich medium (Loebel model) have been developed. In contrast to the energy metabolism of Wayne bacilli, little is known about Loebel bacilli. Here we analysed M. tuberculosis under nutrient-starvation conditions. Upon shifting to the non-replicating state the pathogen maintained a fivefold reduced but constant intracellular ATIP level. Chemical probing of the F(0)F(1) ATIP synthase demonstrated the importance of this enzyme for ATP homeostasis and viability of the nutrient-starved organism. Surprisingly, the specific ATIP synthase inhibitor TMC207 did not affect viability and only moderately reduced the intracellular ATIP level of nutrient-starved organisms. Depletion of oxygen killed Loebel bacilli, whereas death was prevented by nitrate, suggesting that respiration and an exogenous electron acceptor are required for maintaining viability. Nutrient-starved bacilli lacking the glyoxylate shunt enzyme isocitrate lyase failed to reduce their intracellular ATIP level and died, thus establishing a link between ATIP control and intermediary metabolism. We conclude that reduction of the ATIP level might be an important step in the adaptation of M. tuberculosis to non-growing survival.
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