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

Victoria Furió,Iñaki Comas,Luis M Villamayor,Manuela Torres-Puente,Miguel Moreno-Molina,Álvaro Chiner-Oms

doi:10.1038/s42003-021-02846-z

Abstract

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.

Highlights

Efforts to eradicate tuberculosis are hampered by the rise and spread of antibiotic resistance
The low diversity of the M. tuberculosis Complex (MTBC), its clonality, and the fact that clinical resistance is encoded in the chromosome makes M. tuberculosis amenable for phylogenetic association tests[10], which can determine which mutations are associated with resistance in the bacterial phylogeny and are clinically relevant
We provide a combined approach that uses functional genomics and phylogenetic inference from clinical data to provide an in-depth picture of resistance to the first-line antibiotic isoniazid

Summary

Introduction

Efforts to eradicate tuberculosis are hampered by the rise and spread of antibiotic resistance. 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. One way to unveil the genetic basis of resistance is by means of functional genomics, such as transposon mutagenesis approaches This technique involves the genetic alteration of every gene in the genome for explicit genotype–phenotype associations[8,9], revealing more genetic determinants than regular association studies do. We believe this approach will help uncover the resistance determinants for poorly studied antibiotics, as well as deepen our understanding of resistance emergence, spread, and evolution

Methods

Results

Conclusion