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ACS Infect Dis. 2019 Aug 9;5(8):1317-1326. doi: 10.1021/acsinfecdis.9b00008. Epub 2019 May 30.

Comparative Metabolomics between Mycobacterium tuberculosis and the MTBVAC Vaccine Candidate.

Author information

1
Fundación MEDINA, Parque Tecnológico de Ciencias de la Salud , Avenida del Conocimiento 34 , 18016 Granada , Spain.
2
Departamento de Genética y Microbiología, Facultad de Medicina, Universidad de Murcia , Instituto Murciano de Investigación Biosanitaria (IMIB), Campus de Espinardo , 30100 Murcia , Spain.
3
Grupo de Genética de Micobacterias, Departamento de Microbiología y Medicina Preventiva , Facultad de Medicina, Universidad de Zaragoza , IIS Aragón, C/Domingo Miral s/n, 50019 Zaragoza , Spain.
4
CIBER Enfermedades Respiratorias , Instituto de Salud Carlos III , 28029 Madrid , Spain.
5
Servicio de Microbiología , Hospital Universitario Miguel Servet , Paseo Isabel la Católica 1-3 , 50009 Zaragoza , Spain.
6
Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia , Universidad de Granada , Campus Universitario de Cartuja, 18071 Granada , Spain.
7
Instituto de Biocomputación y Física de Sistemas Complejos (BIFI) , C/Mariano Esquillor, Edificio I + D, Campus Río Ebro , 50018 Zaragoza , Spain.

Abstract

MTBVAC is a live attenuated M. tuberculosis vaccine constructed by genetic deletions in the phoP and fadD26 virulence genes. The MTBVAC vaccine is currently in phase 2 clinical trials with newborns and adults in South Africa, one of the countries with the highest incidence. Although MTBVAC has been extensively characterized by genomics, transcriptomics, lipidomics, and proteomics, its metabolomic profile is yet unknown. Accordingly, in this study we aim to identify differential metabolites between M. tuberculosis and MTBVAC. To this end, an untargeted metabolomics approach based on liquid chromatography coupled to high-resolution mass spectrometry was implemented in order to explore the main metabolic differences between M. tuberculosis and MTBVAC. As an outcome, we identified a set of 34 metabolites involved in diverse bacterial biosynthetic pathways. A consistent increase in the phosphatidylinositol species was observed in the vaccine candidate relative to its parental strain. This phenotype resulted in an increased production of phosphatidylinositol mannosides, a novel PhoP-regulated phenotype in the most widespread lineages of M. tuberculosis. This study represents a step ahead in our understanding of the MTBVAC vaccine, and some of the differential metabolites identified in this work might be used as potential vaccination biomarkers.

KEYWORDS:

live attenuated vaccine; phoP; phosphatidylinositol mannosides; vaccination biomarkers; virulence

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