The overarching goal of the Broad TB-ARC project is to identify the entire complement of naturally occurring mutations that are responsible for drug resistance (DR) in clinical Mycobacterium tuberculosis (Mtb).
The plan is to create a comprehensive catalog of DR-conferring mutations by sequencing large numbers of geographically and phenotypically diverse M. tuberculosis complex strains that have been quantitatively characterized for their resistance to a broad spectrum of first and second line antibiotics. The DR catalog will provide a critical resource for addressing some of the most pressing needs in treating tuberculosis (TB) in the clinic:
- Rapid tests for accurate diagnosis of drug resistance in TB to guide treatment
- Identifying new targets for developing improved anti-TB therapeutics
Among bacterial diseases, TB is the leading cause of death worldwide, with an estimated 1.3 million deaths attributed to TB in 2008. Though historically treatable with standard first-line anti-TB therapy (primarily rifampin, isoniazid, pyrazinamide and sometimes ethambutol), new strains are emerging that are resistant to some and, in some reports, all first and second line antibiotics (fluoroquinolones and aminoglycosides). The inability of clinicians to quickly and accurately determine the DR profile of strains associated with new clinical cases of TB further confounds TB treatment and control leading to long delays in treatment and, worse yet, treatment with unnecessary drugs that increase the opportunity for new DR forms of the bacterium to arise and spread.
At present the knowledge of DR-mutations is woefully incomplete. The fact that we can only identify 85% of the causative mutations for isoniazid resistance, one of the best-studied drugs for mechanism of action in Mtb, underscores the need for a massive effort to comprehensively identify the mutations associated with DR in TB. These mutations, in turn, will become the basis for new tests for resistance.
A further concern is that the DR strains are showing extremely high levels of virulence, both in their ability to rapidly spread from person to person as well as causing rapid disease progression. Thus, there is an urgent need to identify those compensatory mutations that allow DR organisms to thrive as rampantly disseminating, highly successful pathogens. These compensatory mutations will appear as part of the DR catalog by virtue of their association with resistance phenotypes.
To create the needed catalog of DR mutations, Broad researchers are working in partnership with leading TB clinical researchers who hold collections of phenotypically characterized Mtb strains from patients across the globe. These geographically disparate collections of strains will allow identification of DR-causing mutations that are common and distinct among different Mtb genetic backgrounds (lineages).
The data sets are
- TB-ARC Belarus — 143 strain variant files — Comparative sequence analysis of M. tuberculosis isolates from Patients with multi- and extensively drug resistant tuberculosis in Belarus
- TB-ARC CDRC — 179 strain variant files — Whole genome sequencing of clinical strains of M. tuberculosis
- TB-ARC India — 223 strain variant files — Whole Genome Sequencing for understanding TB transmission and evolution of drug resistant mutations in South India
- TB-ARC Iran — 32 strain variant files — Genomic changes at XDR and TDR M. tuberculosis bacilli
- TB-ARC K-RITH II — 182 strain variant files — Identifying Mechanisms of Drug Resistance in M. tuberculosis
- TB-ARC K-RITH KwaZulu-Natal — 219 strain variant files — Characterization of M. tuberculosis Resistance Through Whole Genome Sequence Analysis to Support Diagnostic Development, Drug Discovery, and Molecular Epidemiology
- TB-ARC M. bovis — 8 strain variant files — Genome-scale Global Population Genetic Frameworks of M. bovis
- TB-ARC Mali — 92 strain variant files — A Proposal to Compare the Genomes of MDR and Susceptible M. africanum and M. tuberculosis from Mali
- TB-ARC Moldova — 95 strain variant files— Sequencing M. tuberculosis isolates from the Republic of Moldova to characterize transmission dynamics and improve control of drug-resistant TB
- TB-ARC MRC SA — 189 strain variant files — Preserving Effective TB Treatment Study (PETTS) Samples from the South African Medical Research Council for sequencing
- TB-ARC NTU Taiwan — 40 strain variant files — Understanding Resistance to Fluoroquinolones in the Treatment of MDR TB in Taiwan
- TB-ARC Romania — 34 strain variant files— Romanian clinical isolates of multi-drug resistant Tuberculosis strains
- TB-ARC Sweden — 150 strain variant files — Whole Genome Sequencing of Swedish MDR-TB strains
Data downloads for all variant files:
See instructions on each project page to view individual SNP files on the PATRIC genome browser.