Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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Record number 551899
Title Modeling Host-Pathogen Interaction to Elucidate the Metabolic Drug Response of Intracellular Mycobacterium tuberculosis
Author(s) Rienksma, Rienk A.; Schaap, Peter J.; Martins Dos Santos, Vitor A.P.; Suarez-Diez, Maria
Source Frontiers in Cellular and Infection Microbiology 9 (2019). - ISSN 2235-2988 - 1 p.
DOI https://doi.org/10.3389/fcimb.2019.00144
Department(s) VLAG
Systems and Synthetic Biology
Publication type Refereed Article in a scientific journal
Publication year 2019
Keyword(s) antibiotics - drug response - flux balance analysis - host-pathogen interaction - metabolic model - Mycobacterium tuberculosis
Abstract

Little is known about the metabolic state of Mycobacterium tuberculosis (Mtb) inside the phagosome, a compartment inside phagocytes for killing pathogens and other foreign substances. We have developed a combined model of Mtb and human metabolism, sMtb-RECON and used this model to predict the metabolic state of Mtb during infection of the host. Amino acids are predicted to be used for energy production as well as biomass formation. Subsequently we assessed the effect of increasing dosages of drugs targeting metabolism on the metabolic state of the pathogen and predict resulting metabolic adaptations and flux rerouting through various pathways. In particular, the TCA cycle becomes more important upon drug application, as well as alanine, aspartate, glutamate, proline, arginine and porphyrin metabolism, while glycine, serine, and threonine metabolism become less important. We modeled the effect of 11 metabolically active drugs. Notably, the effect of eight could be recreated and two major profiles of the metabolic state were predicted. The profiles of the metabolic states of Mtb affected by the drugs BTZ043, cycloserine and its derivative terizidone, ethambutol, ethionamide, propionamide, and isoniazid were very similar, while TMC207 is predicted to have quite a different effect on metabolism as it inhibits ATP synthase and therefore indirectly interferes with a multitude of metabolic pathways.

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