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Acetate Fermentation facilitates survival of Mtb when respiration is inhibited

ABSTRACT: Respiratory ATP-synthesis is at present the only known mechanism for ATP synthesis in Mtb. This makes Mtb particularly vulnerable to inhibition of respiratory ATP synthase inhibitors such as TMC207, a novel compound for treatment of tuberculosis. We now provide first evidence that Mtb possesses a pathway that is fermentative in nature that could compensate lack of respiratory ATP synthesis. We identified acetate as a fermentation product in Mtb. Production of acetate was mediated by phosphotransacetylase (Pta) and acetate kinase (AckA). In acetate fermenting Mtb cultures, ATP levels remained stable despite inhibition of respiratory ATP synthase. Deletion of the PtaAckA pathway in Mtb decreased ATP content and impaired survival. This study provides evidence that in Mtb substrate level phosphorylation can compensate lack of oxidative phosphorylation, and thus facilitates survival of Mtb in the absence of respiration. Acetate fermentation contributes to adaptation to respiration-limiting conditions, and plays an important role in the emerging field of fermentative metabolism of Mtb.

ORGANISM(S): Mycobacterium tuberculosis Mycobacterium tuberculosis H37Rv

PROVIDER: GSE35484 | GEO | 2012/12/31

SECONDARY ACCESSION(S): PRJNA152375

REPOSITORIES: GEO

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Project description:Pathogens that grow during infections must cope with the reactive oxygen species (ROS) released by host immune cells. Among the different strategies to prevent oxidative damage during infections, pathogenic bacteria have evolved mechanisms to reduce respiration and other cellular processes that are particularly sensitive to free radicals, obtaining energy preferentially by undergoing to fermentative metabolism. As fermentation produces fewer ATP per glucose than respiration, bacteria ensure an appropriate supply of energy by increasing the glycolytic flux. The opportunistic human pathogen Staphylococcus aureus is one such microbe but the underlying mechanism that enables S. aureus to induce fermentation during infections is still unclear. Here we show that the ComK-like regulator of natural competence that is present in many gram-positive bacteria is crucial to redirect S. aureus metabolism to fermentation during infection. ComK is cryptic in laboratory conditions but highly induced during infections or in response to infection-related cues, such as ROS. ComK induces the glycolytic flux and glucose consumption rate, a key step to redirect ATP production to fermentation. This licenses fermenting S. aureus to reduce oxidative damage while increasing DNA uptake by natural transformation. As a consequence, a comK-defective mutant shows an accumulation of ROS as well as DNA mutations that lower bacterial survival. This mutant shows no distinctive phenotype in laboratory conditions but is unable to cause infection in vertebrates or invertebrate infection models. ComK-mediated synchronization of natural transformation to fermentative metabolism may allow S. aureus, and probably other gram-positive bacteria, to use the fermentation acid end products to eliminate bacterial competitors while assimilating their DNA. Assimilated DNA may serve as a source of nucleotides for DNA repair or to promote genetic variability, thereby enabling a successful host colonization of this bacterium.

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Acetate Fermentation facilitates survival of Mtb when respiration is inhibited

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