Whole-genome sequencing analysis of fluoroquinolone resistance acquisition in Mycobacterium tuberculosis

Work Group

Project Lead(s)

Project Status

Ongoing

Project Deliverable

Phylogenetic reconstruction of fluoroquinolone resistance acquisition from whole-genome sequencing data of Mycobacterium tuberculosis

Collaborator Name

Maha Farhat, MD MSc

HMS Department

Center for Computational Biomedicine

Project Description

Tuberculosis (TB), caused by the pathogens of the Mycobacterium tuberculosis complex (MTBC), is a major public health threat causing an estimated 10 million new cases of disease per year. MTBC genomes show no evidence for recombination or horizontal gene transfer. Genomic diversity, including more ancient divergence from the MTBC ancestor and between lineage members, is instead driven predominantly by DNA damage and replication error resulting in chromosomal point mutations. Consequently, antimicrobial resistance frequently arises in MTBC populations as positive selection acts on resistance conferring point mutations. Such resistance mutations can be often identified by observing which mutations repeatedly arise in parallel (homoplastic mutations) within MTBC populations and in different genetic backgrounds using whole genome sequencing (WGS) data from genetically diverse samples. In particular, the class of antimicrobials, fluoroquinolones (FQs), are a mainstay of TB treatment, but their widespread use is compromising their population efficacy. Targeted TB control strategies should be grounded in our understanding of when and how fluroquinolone resistance (FQ-R) emerge, and factors that contribute to its spread, including adaptive evolutionary changes in MTBC.