Indiscriminate use of antibiotics and modern hospitals are often justifiably blamed for the growing specter of antibiotic resistant superbugs. However, a new study presents genomic evidence that at least one hospital-associated superbug acquired its adaptive edge at a timepoint that predates the modern hospital. These findings indicate that selection in another ecological niche is responsible for the hospital associated adaptions of this pathogen, underlining its generalist nature.

“This research has discovered that these hospital-associated strains of antibiotic resistant bacteria are much older than we previously thought and has highlighted their incredible metabolic flexibility combined with numerous mechanisms enhancing their survival under harsh conditions that has allowed them to spread widely across the globe,” says Julian Parkhill, PhD, coauthor on the study and professor in the department of veterinary medicine at the University of Cambridge.

Scientists from Wellcome Sanger Institute, the University of Oslo, and the University of Cambridge have sequenced the common hospital pathogen Enterococcus faecalis in a large set of host species including wild birds, mammals, healthy humans, and hospitalized patients. Using long- and short-read sequencing techniques, the researchers have created an evolutionary timeline of the bacterium and have detected bacterial lineages that survive to this day with the last common ancestor dating back to the 19th century.

“Currently, when patients are admitted to hospital, they are swabbed for some antibiotic resistant bacteria and fungi and are isolated to ensure that infection rates are kept as low as possible. Thanks to this study, it is possible to scrutinize the diversity of E. faecalis and identify those that are more prone to spread within hospitals and thus could cause harm in immunocompromised people. We believe that it could be beneficial to also screen for E. faecalis on admission to hospitals,” says Anna Pöntinen, PhD, co-lead author and postdoctoral fellow at the University of Oslo.

Armed with a collection of 2027 whole-genome sequences from blood and stool samples dating back from an era when there were no antibiotics, to the modern times of multi-drug resistance and pathogenic attributes tailored to a hospital-adapted lifestyle, the authors report a nuanced picture of the gain and loss of bacterial plasmids in the population. The analysis reveals trends of genomic changes that allow this species to adapt to different ecologies, ranging from the human gut to wild birds, including the restrictive niche of the hospital.

These findings are reported in “Apparent nosocomial adaptation of Enterococcus faecalis predates the modern hospital era“—an article published in Nature Communications on March 9, 2021.

Enterococcus faecalis
Enterococcus faecalis [Janice Hane]
“This is the first time we have been able to map out the full evolution of E. faecalis from samples up to 85 years old, which enables us to see the detailed effect of human lifestyles, agriculture and medicines on the development of different bacterial strains. Having the full timeline of evolutionary changes would not have been possible without analytical and sequencing techniques that can be found at the Sanger Institute,” says Jukka Corander, PhD, co-lead author and Associate Faculty member at the Wellcome Sanger Institute.

The study provides evidence that the pathogen E. faecalis can adapt quickly to selection pressures, such as the use of chemicals in farming as well as the development of new medications. This has caused the emergence of different strains of the bacterium in many places worldwide.

Jukka Corander
Jukka Corander, PhD, co-lead author and Associate Faculty member at the Wellcome Sanger Institute.

E. faecalis normally lives in the human intestinal tract without causing any harm to the host (commensal pathogen). However, in an immunocompromised host, the bacterium can cause serious infection. Antibiotic resistant strains of E. faecalis are common in hospitals. It was initially thought that the wide use of antibiotics and other antibacterial control measures in modern hospitals spurred the evolution of these resistant strains.

The team has mapped the evolutionary journey of the bacterium from the sequencing data and created a timeline of when and where different strains developed, including strains resistant to antibiotics. They found that antibiotic resistant strains developed before the widespread use of antibiotics. Therefore, antibiotic use couldn’t have caused these strains to emerge.

Agricultural and early medical practices, such as the use of arsenic and mercury, created selection pressures that influenced the evolution of some of the strains we see now, the authors report.  The team found strains like the hospital-associated antibiotic resistant variants, in wild birds. exemplifying the adaptability and flexibility of E. faecalis at responding to selective pressure.