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Genomic signatures of pre-resistance in Tuberculosis

Researchers have conducted the largest population-level genomic analysis of M. tuberculosis to date, with a view to pre-empt the emergence of resistance.

Mycobacterium tuberculosis is a bacterial infection that affects the lungs. It is estimated to have killed 1 billion people over the last 200 years and was the second leading infectious cause of death in 2020, after COVID-19. Therefore, unsurprisingly, it remains one of the world’s deadliest pathogens. This is partly due to drug resistance to M. tuberculosis, which imposes an unsustainable burden on health programs worldwide. In fact, some strains are so extensively resistant that they are untreatable with existing antibiotic therapy.

Recent advances in bacterial whole-genome sequencing have resulted in a comprehensive catalogue of antibiotic resistance genomic signatures in M. tuberculosis. However, these approaches typically miss the opportunity to pre-empt the emergence of drug resistance and implement preventive measures prior to the spread of antibiotic resistant disease. Additionally, samples for drug-resistant isolates are usually unrepresentative, and thus limit the ability to characterise the evolution and dynamics of drug resistance from a diverse background of ancestral susceptible strains.

Largest population analysis of M. tuberculosis

Recently, a group of researchers led by Great Ormond Street Hospital (GOSH) and the UCL Great Ormond Street Institute of Child Health, in collaboration with the Peruvian Tuberculosis programme and funded by Wellcome and the National Institutes of Health (USA), conducted the largest population level genomic analysis of M. tuberculosis to date. Their results were published in Nature Communications.

The team sequenced the whole genomes from 3,135 isolates sampled from the hyperendemic suburbs of Lima, Peru, over a 17-year period with a view to pre-empt the emergence of resistance. This demonstrated that there are significant differences in the acquisition of drug resistance between lineages, on mono-resistant backgrounds and at the level of nucleotide polymorphisms. Specifically, M. tuberculosis lineage 2 had a higher risk of acquiring resistance than lineage 4, and also acquired resistance to antibiotics more rapidly than lineage 4. 

The researchers then tested and replicated these findings in an independent publicly available data set of 1,027 whole genomes collected in Samara, Russia, and in a collection of 1,573 isolates from multiple countries, to demonstrate that they can be globally generalised.

Pre-resistance of M. tuberculosis polymorphisms

Overall, this population-wide 17 year-long epidemiological study of M. tuberculosis genetics provides the first description and evaluation of pre-resistant polymorphisms in susceptible genotypes that predispose to the acquisition of future drug resistance. Essentially, the researchers identified how to pre-empt drug resistance mutations before they have occurred. Additionally, the 17-year sampling time frame provided a unique opportunity to study drug resistance acquisition dynamics and evolution.

Dr Grandjean, senior author of the international study, said: “We’re running out of options in antibiotics and the options we have are often toxic – we have to get smarter at using what we have to prevent drug resistance. This is the first example of showing that we can get ahead of drug resistance. That will allow us in the future to use the pathogen genome to select the best treatments.”

In the future, prediction of future drug resistance in susceptible pathogens, together with targeted expanded therapy, has the potential to prevent drug resistance emergence in M. tuberculosis and other pathogens.

Arturo Torres Ortiz, first author of the paper, said: “We hope this discovery could provide a way of treating difficult conditions in the future by targeting specific pathogen genomes that are most likely to become drug resistant in the future.”

Image credit: Live Science

More on these topics

Bacteria / Genetic resistance / Tuberculosis