Inactivation of Fructose-1,6-Bisphosphate Aldolase Prevents Optimal Co-catabolism of Glycolytic and Gluconeogenic Carbon Substrates in Mycobacterium tuberculosis
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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.
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Inhibition of FBA impairs M. tuberculosis proliferation and increases the susceptibility of mycobacteria to host responses.
“and the inhibition of FBA impairs M. tuberculosis proliferation and increases the susceptibility to mycobacteria to host responses (92).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [92]
The enzyme fructose-1,6-bisphosphanate aldolase (FBA) is essential for mycobacteria to get access to carbon sources derived from carbohydrates.
“In terms of glucose consumption, the enzyme fructose-1,6-bisphosphanate aldolase (FBA) is essential for mycobacteria to get access to carbon sources derived from carbohydrates, and the inhibition of FBA impairs M. tuberculosis proliferation and increases the susceptibility to mycobacteria to host responses (92).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [92]
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- Authors
- Puckett, S., Trujillo, C., Eoh, H., Marrero, J., Spencer, J., Jackson, M., Schnappinger, D., Rhee, K., & Ehrt, S.
- Affiliations
- Weill Cornell Medicine (US)
- Colorado State University (US)
- Corresponding author
- Ehrt, Sabine
- ORCID
- Venue
- PLoS Pathogens
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-05-22
- Volume
- 10
- Issue
- 5
- Pages
- e1004144
- ISSN
- 1553-7366 (ISSN-L)
- 1553-7374
- PMC
- PMC4031216
- OpenAlex
- W2054225806
- Cited by
- 72
- References
- 45
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 8 · 2021: 9 · 2020: 1 · 2019: 7 · 2018: 8 · 2017: 8 · 2016: 7 · 2015: 11 · 2014: 3
- FWCI
- 6.77
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Pathogens (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Bill and Melinda Gates Foundation (42848, OPP1024065)
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (AI 63446, AI078126, T32AI007621, R01AI063446, R21AI078126)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Health Sciences › Medicine › Surgery › Infectious Diseases and Tuberculosis
- Keywords
- Mycobacterium tuberculosis, fructose-1,6-bisphosphate aldolase, glycolysis, gluconeogenesis, butyrate metabolism, carbon source utilization, therapeutic target, persistent infection, tuberculosis pathogenesis
- MeSH terms
- Animals, Butyrates, Female, Fructose-Bisphosphate Aldolase, Gluconeogenesis, Glycolysis, Metabolism, Mice, Inbred C57BL, Mycobacterium tuberculosis, Gene Deletion, Organisms, Genetically Modified, Carbohydrate Metabolism, Mice, Metabolome
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