An evolutionary functional genomics approach identifies novel candidate regions involved in isoniazid resistance in Mycobacterium tuberculosis

12 páginas, 4 figuras, 1 tabla
Efforts to eradicate tuberculosis are hampered by the rise and spread of antibiotic resistance. Several large-scale projects have aimed to specifically link clinical mutations to resistance phenotypes, but they were limited in both their explanatory and predictive powers. Here, we combine functional genomics and phylogenetic associations using clinical strain genomes to decipher the architecture of isoniazid resistance and search for new resistance determinants. This approach has allowed us to confirm the main target route of the antibiotic, determine the clinical relevance of redox metabolism as an isoniazid resistance mechanism and identify novel candidate genes harboring resistance mutations in strains with previously unexplained isoniazid resistance. This approach can be useful for characterizing how the tuberculosis bacilli acquire resistance to new antibiotics and how to forestall them.
This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programs 638553 (TB-ACCELERATE), SAF2016-77346-R from Ministerio de Economía y Competitividad (Spanish Government) and AICO/2018/113 from Generalitat Valenciana (to I.C.). M.M.-M. is recipient of a FPI grant from the Ministerio de Economía y Competitividad (Spanish Government, code BES-2017-079656). V.F. was recipient of a post-doctoral research grant from the Ministerio de Economía y Competitividad (Spanish Government, code FPDI-2013-18757). Action cofinanced by the European Union through the Operational Program of European Regional Development Fund (ERDF) of Valencia Region (Spain) 2014-2020.