Next Generation Sequencing Applications for Drug-Resistant Tuberculosis

Drug-resistant tuberculosis (DR-TB) is a significant problem for government tuberculosis control programs around the globe. Complicating these problems, the fields of DR-TB diagnosis and treatment have encountered tremendous challenges over the last five years. Thankfully, next generation sequencing technology has played a key role in responding to these challenges, transforming disadvantages into new opportunities.

The team of researchers behind the recent Microbiology article “Application of Next Generation Sequencing for Diagnosis and Clinical Management of Drug-Resistant Tuberculosis” began their review of evolving DR-TB industry developments with an imperative from the World Health Organization, which stresses the supreme importance of early diagnosis and comprehensive drug susceptibility testing (DST) for tuberculosis patients worldwide.

The article’s authors go on to identify whole genome sequencing (WGS) and other advanced forms of next generation sequencing as exceptional tools for executing molecular-based DST for tuberculosis. WGS has proven particularly effective in drug resistance prediction for the common treatments of Mycobacterium tuberculosis. As this particularly devastating form of tuberculosis continues to develop problematic drug resistance mechanisms, the enormous potential of next generation sequencing to aid in DST cannot be ignored. “Application of Next Generation Sequencing for Diagnosis and Clinical Management of Drug-Resistant Tuberculosis” discusses various resistance problems that have recently arisen among the new and repurposed pharmaceuticals Bedaquiline, Clofazimine, Linezolid, Delamanid, and Pretomanid.

In the face of increased resistance to these and other tuberculosis drugs, next generation sequencing holds tremendous promise in DST for tuberculosis, enabling clinicians to pursue the most effective course of treatment for each individual patient. Roughly two decades after the first complete sequencing of the Mycobacterium genome, WGS has become what the authors of “Application of Next Generation Sequencing for Diagnosis and Clinical Management of Drug-Resistant Tuberculosis” call a “robust clinical diagnostic platform for DR-TB.”

In fact, a 2021 study found that WGS offers a 20% added benefit when compared with classic genotypic assays used in the detection of DR-TB. Another study determined that, by centralizing the sequencing laboratory within the clinical setting, healthcare facilities could readily adopt WGS as a routine part of the TB diagnosis process.

Until recently, the lack of comprehensive genomic databases related to DR-TB detection has proven a substantial hurdle to the use of WGS among tuberculosis specialists in the clinical setting. In particular, there has been a poor correlation of genomic information between Mycobacterium genomic and phenotypic drug susceptibility results.

Over the last few years, however, there have considerable efforts to overcome the problem of genotypic-phenotypic correlation and generally curate genomic data for clinical relevance. Open access databases such as the Comprehensive Resistance Prediction for Tuberculosis and International Consortium (CRyPTIC) and Relational Sequencing (ReSeq) TB now provide access to isolates from a range of geographic locations.

Another big step forward for WGS as a guidance tool for DR-TB treatment is the successful sequencing of clinical specimens from expectorated sputum. Until now, WGS has required the culturing of specimens in a mycobacterial growth indicator tube (MGIT). By sequencing directly from sputum, clinicians can skip the MGIT process and deliver comprehensive DR-TB resistance profiling that fits into a reasonable tuberculosis treatment timeline.

Last but certainly not least, a new, alternative approach to next-generation sequencing using targeted genomic panels holds tremendous promise when it comes to addressing only the specific genes that are involved with tuberculosis drug-resistance. This highly targeted technique extends both specificity and depth of coverage for the detection of the single nucleotide polymorphisms associated with DR-TB. Targeted genomic panels also offer distinct advantages over WGS when it comes to ensuring adequate DNA quantity and protecting samples from contamination.

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