In Search for the Origins of Antibiotic Resistance – Scientists Discover 18 Never-Before-Seen Species of Gut Microbes

Researchers have made progress against citrus greening disease by developing hybrid citrus trees that produce desirable orange-like fruit and resist the disease. Through genetic analysis, they’ve created tools for early flavor profile screening, marking a significant step in ensuring future hybrids combine disease tolerance with the essential sweet orange flavor.

Antibiotic-resistant infection is projected to catch up to cancer as the leading cause of death by 2050, making understanding and limiting the spread of antibiotic-resistant bacteria a priority worldwide.

In a paper recently published in the Proceedings of the National Academy of Sciences (PNAS), a research team co-led by Michael S. Gilmore, Ph.D., Chief Scientific Officer at Mass Eye and Ear, describes the discovery of 18 never-before-seen species of bacteria of the Enterococcus type that contain hundreds of new genes – findings that may offer new clues into antibiotic resistance as scientists hunt for ways to curb these infections.

Enterococci are leading causes of multidrug-resistant infections, particularly following surgery and in hospitalized patients. The infections can be lethal and contribute to more than $30 billion annually in added healthcare costs.

The Importance of Antibiotics

“Over the past 75 years, antibiotics have saved hundreds of millions of lives and have contributed greatly to the success of all types of surgery,” said Gilmore, who also is director of the Infectious Disease Institute at Harvard Medical School. “Over the past 30 years, however, many of the most problematic bacteria have become increasingly resistant to antibiotics and this is now reaching crisis proportions. Our findings may improve understanding of how resistance genes spread to hospital bacteria and threaten human health.”

Discovered in the 1920s, antibiotics like penicillin are compounds naturally produced by microbes in the soil. Gilmore notes that antibiotic-producing microbes thrive in rotting leaves and plant matter on the forest floor and give forest soil its smell.

The Role of Insects in Antibiotic Resistance

Gilmore and Ashlee Earl, Ph.D., director of the Bacterial Genomics Group at Broad, assembled an international team of scientists, including elite adventurers, to scour remote corners of the globe for scat, soil and other samples that would likely contain bacteria of the Enterococcus type. The diversity of specimens they collected spanned samples from penguins migrating through sub-Antarctic waters, duiker and elephants from Uganda; insects, bivalves, sea turtles, and wild turkeys from Brazil to the United States; kestrel and vultures from Mongolia; wallaby, swans, and wombats from Australia; and zoo animals and wild birds from Europe.

The team’s collection efforts had previously led to the discovery of new classes of bacterial toxins and showed that Enterococcus bacteria arose about 425 million years ago when the first animals, ancestors of millipedes and worms, came onto land. They likely dominated the planet for about 50 million years before four-legged animals came ashore.

Adventure Scientist Stevie Anna Plummer with scat and water samples collected during a 2016 Nepal expedition to collect samples for the Global Microbe Study. Credit: Adventure Scientists (photo by Paul Amos)

Their most recent collections expanded the genus diversity of enterococcal strains by more than 25 percent and in doing so, uncovered more clues, revealing that insects and other invertebrates are likely by far the greatest natural source for enterococci bacteria, including species that are naturally antibiotic-resistant.

“Until recently, most of what we’ve understood about the genetics of enterococcus come from those that make us sick, and that’s a problem — like trying to understand darkness without ever seeing the light,” said Earl. “Expanding our view to include those from outside of hospitals, with the help of citizen scientists, gave us the contrast we needed to identify how they make people sick in the hospital, and also gives the public the chance to co-own solutions.”

Gilmore posits that insects have been eating the rotting plant material, and naturally giving themselves a dose of the antibiotics in the process. He hypothesizes that for hundreds of millions of years, bacteria in the guts of these insects like Enterococcus have been exposed to those antibiotics and have become resistant. In the 1940s and ’50s, when humans first began taking antibiotics, the resistances were already in the environment and worked their way into the bacteria that cause human infection.

“The COVID-19 pandemic revealed that nature contains many infectious risks for humans,” said Gilmore. “This study shows that insects and their relatives in nature are a large and uncharacterized reservoir of undiscovered genes in microbes closely related to those that cause some of the most antibiotic-resistant infections.”

Reference: “Global diversity of enterococci and description of 18 previously unknown species” by Julia A. Schwartzman, Francois Lebreton, Rauf Salamzade, Terrance Shea, Melissa J. Martin, Katharina Schaufler, Aysun Urhan, Thomas Abeel, Ilana L. B. C. Camargo, Bruna F. Sgardioli, Janira Prichula, Ana Paula Guedes Frazzon, Gonzalo Giribet, Daria Van Tyne, Gregg Treinish, Charles J. Innis, Jaap A. Wagenaar, Ryan M. Whipple, Abigail L. Manson, Ashlee M. Earl and Michael S. Gilmore, 28 February 2024, Proceedings of the National Academy of Sciences.
DOI: 10.1073/pnas.2310852121

This project was supported by the Harvard-wide Program on Antibiotic Resistance, NIH/NIAID grant AI083214 and U19AI110818 to the Broad Institute. Portions of the work were supported by a Research Sabbatical grant to Gilmore from Research to Prevent Blindness to explore the origins of antibiotic resistance. Schwartzman was supported by the NIH Ruth Kirschstein fellowship F32GM121005.