Scientists have spotted signs of ‘pre-resistance’ in bacteria for the first time – signs that some bacteria are likely to become resistant to antibiotics in the future – in a new study led by researchers from UCL and of the Great Ormond Street Hospital.
The findings, published in Nature Communicationwill allow future physicians to select the best treatments for bacterial infections.
The team led by Great Ormond Street Hospital (GOSH) and UCL Great Ormond Street Institute of Child Health, in collaboration with the Peruvian Tuberculosis Program and funded by Wellcome and the National Institutes of Health (USA), sequenced the complete genomes of more than 3,000 tuberculosis (TB), tracing TB infections in patients over nearly two decades.
Mycobacterium tuberculosis (TB) is a bacterial infection that largely affects the lungs. It was the second infectious cause of death after COVID-19 in 2020, killing 1.5 million people. It can be cured if treated with the right antibiotics, but treatment is long and many of those most at risk do not have access to adequate health care. Drug-resistant tuberculosis can develop when people do not complete their full course of treatment, or when drugs are unavailable or of poor quality.
Multidrug-resistant tuberculosis represents a huge and unsustainable burden and fully drug-resistant strains have been detected in a handful of countries. As health systems struggle to cope with the pandemic, progress in TB treatment around the world has slowed.
To develop a better understanding and ultimately better treatments for TB, this new research has identified for the first time how to anticipate drug resistance mutations before they occur. The researchers called this concept “pre-resistance”: when a pathogenic organism, such as a virus or bacteria, has an inherent higher risk of developing drug resistance in the future.
By analyzing thousands of bacterial genomes, the study has the potential to be applied to other infectious diseases and paves the way for personalized pathogen ‘genomic therapy’ – where drugs are selected based on the pathogen’s DNA specific to the origin of the disease, preventing drug resistance from developing.
This work is the culmination of 17 years of research in the suburbs of Lima, Peru, where Dr Louis Grandjean, infectious disease consultant at GOSH and associate professor at UCL Great Ormond Street Institute of Child Health, leads a group of research.
The international team compared TB samples from 3,135 different samples to reconstruct a bacterial ‘family tree’ of TB – known as the phylogeny. The team then used computer analysis to identify the ancestral genetic code of bacteria that then developed drug resistance. The team identified key changes associated with the development of resistance by looking at ‘branches’ of the family tree to see which were most likely to develop drug resistance.
The authors described how variations in the TB genome predicted that a particular branch was likely to become drug resistant, then validated their findings in an independent global TB data set.
Dr Grandjean, lead author of the international study, said: “We are running out of options when it comes to antibiotics and the options we have are often toxic – we need to be smarter about using what we have. to prevent drug resistance.
“This is the first example showing that we can get ahead of drug resistance. This will allow us in the future to use the pathogen’s genome to select the best treatments.”
PhD student Arturo Torres Ortiz (UCL Great Ormond Street Institute of Child Health), first author of the paper, said: “We hope this discovery may provide a way to treat difficult conditions in the future by targeting pathogenic genomes that are most likely to become drug resistant in the future.”