Growth Regulation in the Mycobacterial Cell

Cox, Robert A.; Cook, Gregory M.

doi:10.2174/156652407780598584

Cited by 36 publications

(38 citation statements)

References 65 publications

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“…However, these attractive hypotheses await further experimental evidence. These findings therefore support the development of new phenothiazine analogues as a new class of anti-TB drugs (17,19,27,34).…”

Section: Discussionsupporting

confidence: 66%

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The protonmotive force is required for maintaining ATP homeostasis and viability of hypoxic, nonreplicating Mycobacterium tuberculosis

Rao

Alonso

Rand

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

489

537

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The persistence of Mycobacterium tuberculosis despite prolonged chemotherapy represents a major obstacle for the control of tuberculosis. The mechanisms used by Mtb to persist in a quiescent state are largely unknown. Chemical genetic and genetic approaches were used here to study the physiology of hypoxic nonreplicating mycobacteria. We found that the intracellular concentration of ATP is five to six times lower in hypoxic nonreplicating Mtb cells compared with aerobic replicating bacteria, making them exquisitely sensitive to any further depletion. We show that de novo ATP synthesis is essential for the viability of hypoxic nonreplicating mycobacteria, requiring the cytoplasmic membrane to be fully energized. In addition, the anaerobic electron transport chain was demonstrated to be necessary for the generation of the protonmotive force. Surprisingly, the alternate ndh-2, but not -1, was shown to be the electron donor to the electron transport chain and to be essential to replenish the [NAD ؉ ] pool in hypoxic nonreplicating Mtb. Finally, we describe here the high bactericidal activity of the F0F1 ATP synthase inhibitor R207910 on hypoxic nonreplicating bacteria, supporting the potential of this drug candidate for shortening the time of tuberculosis therapy.anaerobic respiration ͉ dormancy ͉ ATP synthase ͉ NADH dehydrogenase ͉ Diarylquinoline

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Section: Discussionsupporting

confidence: 66%

“…This compound targets the F 0 F 1 ATP synthase and is the most promising anti-TB drug candidate currently under investigation (15,20,27). R207910 reduces the time of therapy in animal models (15,28) and shows superior sterilization activity compared with standard anti-TB drugs.…”

Section: Discussionmentioning

confidence: 99%

The protonmotive force is required for maintaining ATP homeostasis and viability of hypoxic, nonreplicating Mycobacterium tuberculosis

Rao

Alonso

Rand

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

489

537

View full text Add to dashboard Cite

show abstract

“…A DC of about 2180 mV is described for Mycobacteria, while anaerobic bacteria are described to establish DC around 2100 mV (10). Membrane potential plays a key role in cell physiological processes.…”

Section: Probes Used For the Analysis Of The Energy Status Of Cellsmentioning

confidence: 99%

Viability states of bacteria—Specific mechanisms of selected probes

2010

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Single cell techniques like flow cytometry combined with viability staining can help to obtain information on viability states of bacteria. Many fluorescent dyes are available for this purpose and can be chosen according to the available excitation source, the species used, and the background of scientific questions and relevant specifications. Within this short overview, we focus on two diverse groups of bacteria: the gram2 Escherichia coli and representatives of the gram+ Mycobacterium to demonstrate differences and similarities in dye uptake principles, processing and binding. We call for attention to possible diverse responses of different species to various viability assays. The cell surface structure of bacteria and the chemical properties of fluorescent probes considerably determine the success of a certain staining practice. Particular focus was drawn on analysis of membrane integrity, uptake of substrates and transformation of fluorogenic substrates. '

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“…Many studies suggest that high protein stability should be evolutionarily advantageous. Firstly, a significant proportion of cellular ATP is used in protein synthesis therefore long protein half-lives should conserve energy (Cox and Cook 2007). Secondly, it is known that less stable proteins populate unfolded states more frequently, and therefore have higher aggregation rates, than more stable proteins (DePristo et al 2005).…”

Section: Introductionmentioning

confidence: 99%

Reconstructed Ancestral Enzymes Impose a Fitness Cost upon Modern Bacteria Despite Exhibiting Favourable Biochemical Properties

et al. 2015

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Ancestral sequence reconstruction has been widely used to study historical enzyme evolution, both from biochemical and cellular perspectives. Two properties of reconstructed ancestral proteins/enzymes are commonly reported-high thermostability and high catalytic activity-compared with their contemporaries. Increased protein stability is associated with lower aggregation rates, higher soluble protein abundance and a greater capacity to evolve, and therefore, these proteins could be considered ''superior'' to their contemporary counterparts. In this study, we investigate the relationship between the favourable in vitro biochemical properties of reconstructed ancestral enzymes and the organismal fitness they confer in vivo. We have previously reconstructed several ancestors of the enzyme LeuB, which is essential for leucine biosynthesis. Our initial fitness experiments revealed that overexpression of ANC4, a reconstructed LeuB that exhibits high stability and activity, was only able to partially rescue the growth of a DleuB strain, and that a strain complemented with this enzyme was outcompeted by strains carrying one of its descendants. When we expanded our study to include five reconstructed LeuBs and one contemporary, we found that neither in vitro protein stability nor the catalytic rate was correlated with fitness. Instead, fitness showed a strong, negative correlation with estimated evolutionary age (based on phylogenetic relationships). Our findings suggest that, for reconstructed ancestral enzymes, superior in vitro properties do not translate into organismal fitness in vivo. The molecular basis of the relationship between fitness and the inferred age of ancestral LeuB enzymes is unknown, but may be related to the reconstruction process. We also hypothesise that the ancestral enzymes may be incompatible with the other, contemporary enzymes of the metabolic network.

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Growth Regulation in the Mycobacterial Cell

Cited by 36 publications

References 65 publications

The protonmotive force is required for maintaining ATP homeostasis and viability of hypoxic, nonreplicating Mycobacterium tuberculosis

The protonmotive force is required for maintaining ATP homeostasis and viability of hypoxic, nonreplicating Mycobacterium tuberculosis

Viability states of bacteria—Specific mechanisms of selected probes

Reconstructed Ancestral Enzymes Impose a Fitness Cost upon Modern Bacteria Despite Exhibiting Favourable Biochemical Properties

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