An international team of scientists headed by researchers at the University of Cambridge has found evidence that a type of antibiotic-resistant superbug, methicillin-resistant Staphylococcus aureus (MRSA), arose in nature 200 years ago, and long before the use of antibiotics in humans and livestock, which has traditionally been blamed for its emergence. The newly reported studies, based on findings from hedgehog surveys, traced the genetic history of the bacteria. The researchers believe that antibiotic resistance evolved in Staphylococcus aureus living on the skin of hedgehogs that also carried the fungus Trichophyton erinacei, which produces its own antibiotics. In effect, hedgehogs carry a fungus and a bacteria on their skin, and the two are locked in a battle for survival.

“This study is a stark warning that when we use antibiotics, we have to use them with care,” said Mark Holmes, PhD, a researcher in the University of Cambridge department of veterinary medicine. “There’s a very big wildlife ‘reservoir’ where antibiotic-resistant bacteria can survive—and from there it’s a short step for them to be picked up by livestock, and then to infect humans.”

The fungus kills MSSA bacteria, while the MRSA bacteria are able to protect themselves against the antibiotics that the fungus produces on the surface of hedgehogs. [Graphic by Adam Sejer]
Holmes is co-senior author of the team’s published paper in Nature, titled, “Emergence of methicillin resistance predates the clinical use of antibiotics,” in which the investigators concluded, “These results underscore the importance of taking a broad One Health perspective on antibiotic resistance that recognizes the role of natural selection in wild animals and the connectivity of natural, agricultural, and human ecosystems in the evolution and spread of antibiotic-resistant pathogens.” The study was carried out by a large international collaboration, including researchers at the University of Cambridge, the Wellcome Sanger Institute, Denmark’s Serum Statens Institut, and the Royal Botanic Gardens, Kew.

The discovery of antibiotics more than 80 years ago has resulted in great improvements in both human and animal health, the authors wrote. “Although antibiotic resistance in environmental bacteria is ancient, resistance in human pathogens is thought to be a modern phenomenon that is driven by the clinical use of antibiotics.” Misuse of antibiotics is now accelerating the process, and antibiotic resistance is rising to dangerously high levels in all parts of the world. “MRSA is one of the most common antibiotic-resistant bacterial pathogens, causing approximately 171,000 invasive infections each year in Europe alone,” the team further noted. “MRSA was first identified in 1960 shortly after the introduction of methicillin (celbenin) as a treatment option against penicillin-resistant S. aureus clones, but was possibly selected for by the clinical use of penicillin over the previous 20 years.”

Methicillin resistance is now seen in many S. aureus clones around the world, in hospitals, in community settings, and in livestock. “This has serious implications for the treatment of severe infections and the World Health Organization now considers MRSA to be a significant threat to human health,” the researchers further commented.

Methicillin resistance in S. aureus is mediated by the antibiotic resistance genes (ARGs) mecA and mecC. Work led by Holmes in 2011 first identified mecC-MRSA in human and dairy cow populations. At the time it was assumed that the strain had arisen in the cows because of the large amount of antibiotics that these livestock are routinely given. Around 1 in 200 of all MRSA infections are caused by mecC-MRSA. Due to its resistance to antibiotics, MRSA is much harder to treat than other bacterial infections. As well as representing a major threat to human health, MRSA is also a major challenge in livestock farming.

Underpinning their newly reported research, Holmes and colleagues were investigating the surprising discovery—emerging from hedgehog surveys from Denmark and Sweden—that up to 60% of hedgehogs carry mecC-MRSA. “Hedgehog surveys from Denmark and Sweden demonstrated a surprisingly high prevalence of MRSA carrying mecC (mecC-MRSA), raising the possibility that the evolution of these bacteria was driven by natural selection in wildlife, as opposed to clinical use of antibiotics,” the authors wrote. The new study also found high levels of MRSA in swabs taken from hedgehogs across their range in Europe and New Zealand.

Photo shows the fungus Trichophyton erinacei growing in the center of an agar plate streaked with MRSA on the left half and methicillin-susceptible Staphylococcus aureus bacteria on the right. The fungus produces antibiotics, which kill methicillin-susceptible Staphylococcus aureus bacteria but not MRSA, resulting in a clear zone on the right with no bacterial growth. [Claire L. Raisen]
The researchers hypothesized that antibiotic resistance evolved in Staphylococcus aureus as an adaptation to having to exist side-by-side on the skin of hedgehogs with the fungus Trichophyton erinacei. “Our hypothesis that the evolution of mecC-MRSA was driven by natural selection is supported by studies from northwestern Europe and New Zealand that showed that hedgehogs are frequently colonized with the dermatophyte T. erinaceid, which produces a penicillinase-labile penicillin-like substance that was recently identified as penicillin G,” they stated.

To test their hypothesis, the researchers looked at the distribution of mecC-MRSA and other S. aureus isolates in hedgehogs in ten European countries and New Zealand. “We sequenced 244 S. aureus isolates from hedgehogs and 913 S. aureus isolates from other sources to infer the evolutionary histories, host dynamics, geographical dispersal patterns and zoonotic potential of the major mecC-MRSA clones in Europe,” they explained.

“Using sequencing technology we have traced the genes that give mecC-MRSA its antibiotic resistance all the way back to their first appearance, and found they were around in the nineteenth century,” said Ewan Harrison, PhD, a researcher at the Wellcome Sanger Institute and the University of Cambridge and a senior author of the study.

He added: “Our study suggests that it wasn’t the use of penicillin that drove the initial emergence of MRSA, it was a natural biological process. We think MRSA evolved in a battle for survival on the skin of hedgehogs, and subsequently spread to livestock and humans through direct contact.”

Since almost all the antibiotics we use today arose in nature, the researchers say it is likely that resistance to them already exists in nature too. Overuse of any antibiotic in humans or livestock will favour resistant strains of the bug, so it is only a matter of time before the antibiotic starts to lose its effectiveness. As the authors commented, “The finding that some human mecC-MRSA isolates probably originate from local hedgehog reservoirs indicates that mecC-MRSA has probably been a cause of sporadic infections in humans for the past 200 years, more than a century before MRSA was first identified in patients in 1960 … The host interactions that lead to zoonotic transmission probably include direct contact with hedgehogs or contact with secondary animal hosts such as dairy cows, as previously shown for T. erinacei (the cause of ‘hedgehog ringworm’ in humans).”

MRSA spreads from hedgehogs to humans, either directly or via domestic animals. [Graphic by Jesper Larsen]
The findings are not a reason to fear hedgehogs, the researchers believe, as humans rarely get infections with mecC-MRSA, even though it has been present in hedgehogs for more than 200 years. ”It isn’t just hedgehogs that harbor antibiotic-resistant bacteria—all wildlife carries many different types of bacteria, as well as parasites, fungi, and viruses,” said Holmes. “Wild animals, livestock and humans are all interconnected: we all share one ecosystem. It isn’t possible to understand the evolution of antibiotic resistance unless you look at the whole system.”

As the researchers further commented, “It seems reasonable to assume that the microbiota of wild animals have greater exposure to the environmental resistome than the human microbiota and are therefore more likely to acquire environmental ARGs. Thus, wild animals might represent a hitherto unrecognized conduit through which environmental ARGs can be transferred to clinical pathogens.”

Acknowledging some limitations to their reported study, the authors concluded, “Together, these results suggest that methicillin resistance emerged in the pre-antibiotic era as a co-evolutionary adaptation of S. aureus to the colonization of dermatophyte-infected hedgehogs. The evolution of clinically relevant antibiotic-resistance genes in wild animals and the connectivity of natural, agricultural and human ecosystems demonstrate that the use of a ‘one health’ approach is critical for our understanding and management of antibiotic resistance, which is one of the biggest threats to global health, food security, and development.”

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