A massive analysis of over 10,000 Mycobacterium tuberculosis bacterial isolates from 23 countries revealed new genes associated with resistance to 13 new and repurposed first- and second-line antibiotics. The work, by Comprehensive Resistance Prediction for Tuberculosis: an International Consortium (CRyPTIC), is described in two new papers published Aug. 11 in the open-access journal PLOS Biology.
Tuberculosis (TB) is a curable and preventable disease; 85% of those affected can be treated successfully with a six month regimen of medication. Despite this, TB has killed more people than other infectious diseases in recent years, and drug-resistant TB is a constant threat. A better understanding of the M. tuberculose variants that confer resistance to antibiotics is important both for better monitoring of resistant strains and for the development of new drugs.
In the first new paper, the researchers described how they assembled an open-access data compendium of 12,289 M. tuberculose isolates, processed in CRyPTIC partner laboratories around the world. Each isolate was sequenced and then tested on a high-throughput grid with varying concentrations of 13 antimicrobials. Of the samples included in the compendium, 6,814 were resistant to at least one drug, including 4,685 samples resistant to multiple drugs or the first-line treatment rifampicin.
In the second paper, the consortium presented the results of a genome-wide association study (GWAS) using data from 10,228 M. tuberculose isolated. For all 13 drugs, the group found unlisted variants associated with significant increases in minimum inhibitory concentration – the lowest concentration of an antibiotic that stops the growth of M. tuberculose. Analysis of this concentration, rather than a binary resistant or non-resistant outcome, allowed the identification of variants that cause only subtle changes in antibiotic response that can be overcome by increasing drug dose. The researchers selected the 20 most important genes that confer resistance to each drug and described in more detail the magnitude of the effect and the variations within these specific genes.
“Our study demonstrates the ability of global partnerships to significantly improve our knowledge of genetic variants associated with antimicrobial resistance in M. tuberculose“, note the authors.
Together, the papers not only uncover specific genes that can be tracked to better understand the resistance landscape of M. tuberculosebut also a framework for future studies on the pathogen.
“The compendium is not designed to measure the prevalence or estimate the ‘true’ error rates of resistance prediction tools; rather, it serves as a resource to accelerate the development of antimicrobial resistance diagnostics by enriching mutation catalogs for [whole genome sequencing] prediction of resistance, improving our understanding of the genetic mechanisms of resistance and identifying important diagnostic gaps and patterns of drug resistance,” the authors state. “The databook is completely open source and we hope it will facilitate and inspire future research for years to come. »
