Bibliographic citations
Fernandez, R., (2022). Efecto de la pirazinamida sobre la ruta biosintética de coenzima A en Mycobacterium tuberculosis bajo condiciones de estrés [Universidad Peruana Cayetano Heredia]. https://hdl.handle.net/20.500.12866/15416
Fernandez, R., Efecto de la pirazinamida sobre la ruta biosintética de coenzima A en Mycobacterium tuberculosis bajo condiciones de estrés []. PE: Universidad Peruana Cayetano Heredia; 2022. https://hdl.handle.net/20.500.12866/15416
@misc{renati/494062,
title = "Efecto de la pirazinamida sobre la ruta biosintética de coenzima A en Mycobacterium tuberculosis bajo condiciones de estrés",
author = "Fernandez Cornejo, Renato Isaias",
publisher = "Universidad Peruana Cayetano Heredia",
year = "2022"
}
Tuberculosis (TB) is an infectious disease caused by the bacillus Mycobacterium tuberculosis (MTB), which can remain in a latent state of infection. Pyrazinamide (PZA), a prodrug, efficiently eliminates the bacilli in a latent state, preventing the relapse of TB. However, the mechanism of action of the active drug, pyrazinoic acid (POA), remains unknown. Recently, a proposed mechanism of action for PZA has become relevant: POA would inhibit the biosynthesis of Coenzyme A, through the degradation of the enzyme L-aspartate decarboxylase (PanD). The binding of POA to PanD would have a weak inhibitory effect, but would promote the degradation of this enzyme by the caseinolytic protease ClpC1-ClpP. This is demonstrated by the fact that POA reduces endogenous levels of PanD, an enzyme that catalyzes the conversion reaction of L-aspartate to β-alanine, one of the initial steps in CoA biosynthesis. In addition, a metabolomic analysis in M. bovis BCG, evaluated the effect of POA on the intermediates of the CoA biosynthetic pathway, observing a reduction in the levels of β-alanine and the other metabolites downstream of the PanD-catalyzed reaction. In vivo, latent MTB bacilli are exposed to stress conditions, the most representative being: acidic pH, starvation and hypoxia. Interestingly, it has been proposed that stressors drive a phenotype shift in MTB, towards a state in which POA targeting is essential for their survival. However, there are still no studies that consider the main stressors present in the MTB latency state in the mechanism of action of PZA. For this reason, the present project proposes to perform a metabolomic analysis to evaluate the effect of PZA on the intermediates of the CoA biosynthetic pathway in MTB, subjected to the main stress factors related to the latency state: acid pH, starvation and hypoxia. Thus, integrating the influence of the stress conditions present in the MTB dormancy state and the proposed mechanism of action of PZA.
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