The accepted wisdom that resistance to antibiotics is a modern phenomenon driven by their overuse is called into question by new research showing the genes that give methicillin-resistant Staphylococcus aureus (MRSA) its superbug status existed in nature long before antibiotics were first deployed in the clinic.

In fact, S. aureus first developed resistance to methicillin around 200 years ago, according to an international consortium of researchers who have traced the genetic family tree of the bacterium.

The findings, published in Nature on January 5, indicate antibiotic resistance emerged in S. aureus as an adaptation to living cheek by jowl on the skin of hedgehogs with the fungus Trichophyton erinacei, which produces its own antibiotics.

"The S. aureus has to have the MRSA gene in order to live on the hedgehog when the fungus is there – that is – a lot of the time," said Mark Holmes, professor of Microbial Genomics and Veterinary Science at Cambridge University, who is senior co-author of the paper. "We believe this happened in the 19th century, because we can date when the S. aureus strain that has the gene separated from other strains" he told BioWorld Science.

Alongside S. aureus isolates that were resistant to antibiotics, the researchers found some S. aureus strains that were sensitive to antibiotics generated by T. erinacei. Holmes said this is a potential source of new antibiotics. "We are continuing to look at S. aureus in animals and looking at fungi that have been grown from hedgehog samples for more antibiotics," he said.

The discovery arose on the back of a survey of hedgehogs in Denmark and Sweden that showed up to 60% of the animals carried MRSA with mecC, a gene which confers resistance to almost all beta-lactam antibiotics, including penicillin, methicillin and cephalosporin.

Following on from this, samples taken from hedgehogs across their range in Europe, and in New Zealand (where hedgehogs were introduced from Europe), also were shown to harbor MRSA.

Although antibiotic resistance in bacteria in the environment is ancient, MRSA in humans was first identified in 1960, shortly after methicillin was introduced as an alternative when S. aureus became resistant to penicillin.

Before the first cases of MRSA were detected in humans, it was first identified in cattle, suggesting the use of antibiotics to treat mastitis was providing a selective advantage and that human infections were the result of zoonotic transmission.

But the results of the hedgehog survey raised the possibility that the evolution of resistance in MRSA was driven by natural selection in wildlife, as opposed to clinical or veterinary use of antibiotics.

The hypothesis was supported by studies showing hedgehogs frequently are colonized with T. erinacei, which produces a penicillin-like substance called penicillin G (or benzylpenicillin).

To test this hypothesis, the researchers assessed the distribution of mecC-MRSA and other S. aureus isolates from hedgehogs in 10 countries in Europe and in New Zealand. They sequenced the genomes of 244 S. aureus samples from hedgehogs and 913 from other sources to trace the evolutionary history, host dynamics and geographic dispersal patterns.

They also studied the sequences to assess zoonotic potential, identifying mobile genetic elements that encoded human and ruminant specific immune modulators that are involved in immune switching events.

Potential mechanisms for the natural selection of mecC-MRSA by T. erinacei were evaluated by scouring the genomes for beta-lactam biosynthetic genes and by screening the fungus for production of beta lactams and antibiotic activity, against a panel of S. aureus strains.

"We 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 19th century," said Ewan Harrison, research associate at the Wellcome Sanger Institute at Cambridge University, senior co-author of the paper.

"Our study suggests 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," Harrison said.

Natural reservoir

The findings indicate that mecC-MRSA has been a cause of sporadic infections in humans over the past two centuries, long before MRSA was first identified in patients in 1960. Hedgehogs are a natural reservoir, and are likely to be the primary host in some countries.

For example, in Denmark, prevalence in hedgehogs is considerably higher than in cattle, sheep and goats. Before the study, dairy cows were thought to be the most likely reservoir and a major source of zoonotic infections in humans. On the basis of this latest research, it appears cows and other domesticated animals are intermediate hosts.