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Inactivation of fructose-1,6-bisphosphate aldolase prevents optimal co-catabolism of glycolytic and gluconeogenic carbon substrates in Mycobacterium tuberculosis.

TitleInactivation of fructose-1,6-bisphosphate aldolase prevents optimal co-catabolism of glycolytic and gluconeogenic carbon substrates in Mycobacterium tuberculosis.
Publication TypeJournal Article
Year of Publication2014
AuthorsPuckett S, Trujillo C, Eoh H, Marrero J, Spencer J, Jackson M, Schnappinger D, Rhee K, Ehrt S
JournalPLoS Pathog
Volume10
Issue5
Paginatione1004144
Date Published2014 May
ISSN1553-7374
KeywordsAnimals, Butyrates, Carbohydrate Metabolism, Female, Fructose-Bisphosphate Aldolase, Gene Deletion, Gluconeogenesis, Glycolysis, Metabolism, Metabolome, Mice, Mice, Inbred C57BL, Mycobacterium tuberculosis, Organisms, Genetically Modified
Abstract

Metabolic pathways used by Mycobacterium tuberculosis (Mtb) to establish and maintain infections are important for our understanding of pathogenesis and the development of new chemotherapies. To investigate the role of fructose-1,6-bisphosphate aldolase (FBA), we engineered an Mtb strain in which FBA levels were regulated by anhydrotetracycline. Depletion of FBA resulted in clearance of Mtb in both the acute and chronic phases of infection in vivo, and loss of viability in vitro when cultured on single carbon sources. Consistent with prior reports of Mtb's ability to co-catabolize multiple carbon sources, this in vitro essentiality could be overcome when cultured on mixtures of glycolytic and gluconeogenic carbon sources, enabling generation of an fba knockout (Δfba). In vitro studies of Δfba however revealed that lack of FBA could only be compensated for by a specific balance of glucose and butyrate in which growth and metabolism of butyrate were determined by Mtb's ability to co-catabolize glucose. These data thus not only evaluate FBA as a potential drug target in both replicating and persistent Mtb, but also expand our understanding of the multiplicity of in vitro conditions that define the essentiality of Mtb's FBA in vivo.

DOI10.1371/journal.ppat.1004144
Alternate JournalPLoS Pathog
PubMed ID24851864
PubMed Central IDPMC4031216
Grant ListR01 AI063446 / AI / NIAID NIH HHS / United States
AI078126 / AI / NIAID NIH HHS / United States
AI63446 / AI / NIAID NIH HHS / United States
T32 AI007621 / AI / NIAID NIH HHS / United States

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