First Step Taken to Predicting When Bacteria May Become Resistant

Rob Hicks

December 16, 2021

The end of the battle against antibiotic resistance may be one step nearer as scientists identify signs in bacteria that mean they are likely to become resistant to antibiotics in the future.

This is the very first time there has been the opportunity to predict in advance when bacteria may become resistant to specific antibiotics, offering hope that in the future it may be possible to pre-empt drug resistance mutations in bacteria before these occur – a concept the scientists call 'pre-resistance', that is when a disease-causing organism, such as a virus or bacteria, has a greater inherent risk of developing resistance to drugs in the future. It is hoped that this will in turn enable doctors in future to select the best treatments for bacterial infections.

17 Years

The research, led by scientists at Great Ormond Street Hospital (GOSH) and the UCL Great Ormond Street Institute of Child Health, in collaboration with the Peruvian Tuberculosis programme, and published in the journal Nature Communications, involved tracing tuberculosis (TB) infections back through patients over 17 years, and sequencing the full genomes of over 3000 TB samples. Using these samples, the scientists reconstructed a TB bacterial 'family tree' – known as phylogeny. Computational analysis was then used to identify the ancestral genetic code of bacteria that then went on to develop drug resistance. By looking through the 'branches' of the family tree the team were able to identify the key changes associated with antibiotic resistance development, enabling them to determine which were most likely to develop drug resistance in the future.

Second Most Common Infectious Killer

In 2020, TB was the second most common infectious cause of death, after COVID-19, killing 1.5 million people. Despite effective antibiotic treatment being available, TB treatment is lengthy and many at risk people do not have access to adequate healthcare. When people do not finish their full treatment course, or when those drugs available are of poor quality, resistant TB can develop. Indeed, multi-drug resistant TB is a major healthcare challenge globally.

Dr Grandjean, senior author of the international study, and consultant in infectious diseases at GOSH and associate professor at UCL Great Ormond Street Institute of Child Health, 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."

Genomic Therapy

The authors described how variations in the TB genome predicted that a particular branch would likely become drug resistant, and then validated their findings in an independent global TB data set.

It is hoped that the process of analysing thousands of bacterial genomes when applied to other infectious diseases will pave the way towards being able to select drugs based on the DNA of the specific pathogen - personalised pathogen ‘genomic therapy’ - hence preventing drug resistance from developing.

PhD student Arturo Torres Ortiz (UCL Great Ormond Street Institute of Child Health), 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."

Dr Grandjean emphasised how, "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."

The study was funded by Wellcome and the National Institutes of Health (USA).

Torres Ortiz, A., Coronel, J., Vidal, J.R. et al. Genomic signatures of pre-resistance in Mycobacterium tuberculosis. Nat Commun 12, 7312 (2021). https://doi.org/10.1038/s41467-021-27616-7.

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