The genetic culprits responsible for the spread of multidrug resistance (MDR) in bacteria have been identified by new research mapping 100 years of bacterial evolution.
Experts at EMBL’s European Bioinformatics Institute, the Wellcome Sanger Institute, the University of Bath, and their collaborators, analysed over 40,000 plasmids from historical and present-day bacterial samples taken across six continents – the largest dataset of its kind.
Plasmids are small, circular DNA molecules in bacteria that allow different strains to share genetic information.Plasmids help bacteria adapt to various environments.
In this study, published in the journal Science, researchers found that a minority of plasmids causes most of the multidrug resistance in the world. In the future, developing ways to target these plasmids could lead to new therapies to combat treatment-resistant infections worldwide.
“Our research combines historical and modern-day data to give a new perspective on the evolutionary lifestyles that different plasmids can have, whether this be changing slowly, completely merging with other plasmids, or disappearing and leaving genetic fragments that are then ‘recycled for parts’,” said Zamin Iqbal, Professor of Algorithmic and Microbial Genomics at the University of Bath and former Group Leader at EMBL-EBI. “Through our research, we can see the impact of human antibiotic use and the shadow of other selective forces, which also challenge bacteria and their plasmids.”
Currently, treatment-resistant infections cause at least one million deaths worldwide every year, with this number expected to rise. While some bacteria and fungi carry antimicrobial resistance (AMR) genes naturally, the emergence and spread of MDR and AMR genes has been consistently linked to the use of antibiotics.
In this study, researchers were able to analyse bacterial samples from as far back as 1917, a time before the discovery of antibiotics. The team found that the ancestral plasmids that went on to become global spreaders of AMR genes did not contain resistance genes initially. They evolved to gain this resistance as the use of antibiotics grew. Their descendants, a relatively small group of modern plasmids, now confer resistance to both first-line and last-resort antibiotics, making them a huge threat to human health.
The team also developed a model for plasmid evolution, highlighting the three distinct pathways plasmids can take.
The modern plasmids that contain MDR genes rose from two of these pathways. Either they were formed by AMR genes being inserted into an existing plasmid structure, or these plasmids were the result of fusion with another plasmid. The plasmids formed by fusion are also highly transferable between different species of bacteria.
As these plasmids are found across multiple different bacterial species, developing ways to target the AMR-carrying plasmids could lead to new therapies to combat multiple treatment-resistant infections worldwide.
“Plasmids are key drivers of bacterial survival against antibiotics. By going back in time through unique historical collections, we reveal how plasmids adapted to the antibiotic era and the evolutionary journey that transformed a minority of them into the global multidrug-resistant vectors driving the antimicrobial resistance crisis we face today,” Adrian Cazares, ESPOD Fellow at EMBL-EBI and Wellcome Sanger Institute. “Our findings show that the widespread use of antibiotics fundamentally reshaped the genetic landscape of plasmids, and the way bacteria fight against antimicrobial treatment, and are a stark reminder that our actions have a profound and lasting impact on bacterial evolution.”
This press release was originally published on the Wellcome Sanger Institute website.
EditScience 25 September 2025
10.1126/science.adr1522
