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University of Oregon researchers have uncovered a molecule produced by yeast living on human skin that showed potent antimicrobial properties against a pathogen responsible for a half-million hospitalizations annually in the United States.

It's a unique approach to tackling the growing problem of antibiotic-resistant bacteria. With the global threat of drug-resistant infections, fungi inhabiting human skin are an untapped resource for identifying new antibiotics, said Caitlin Kowalski, a postdoctoral researcher at the UO who led the study.

Described in in Current Biology, the common skin fungus Malassezia gobbles up oil and fats on human skin to produce fatty acids that selectively eliminate Staphylococcus aureus. One out of every three people has Staphylococcus aureus harmlessly dwelling in their nose, but the bacteria are a risk factor for serious infections when given the opportunity: open wounds, abrasions and cuts. They're the primary cause of skin and soft tissue infections known as staph infections.

Staphylococcus aureus is also a hospital superbug notorious for being resistant to current antibiotics, elevating the pressing need for new medicines.

"There are lots of studies that identify new antibiotic structures," Kowalski said, "but what was fun and interesting about ours is that we identified (a compound) that is well-known and that people have studied before."

The compound is not toxic in normal lab conditions, but it can be potent in conditions that replicate the acidic environment of healthy skin.

"I think that's why in some cases we may have missed these kinds of antimicrobial mechanisms," Kowalski added, "because the pH in the lab wasn't low enough. But human skin is really acidic."

Humans play host to a colossal array of microorganisms, known as the microbiome, but we know little about our resident fungi and their contributions to human health, Kowalski said. The skin microbiome is of special interest to her because while other body parts crowd dozens of different fungi, the skin is dominantly colonized by one kind known as Malassezia.

Malassezia can be associated with cases of dandruff and eczema, but it's considered relatively harmless and a normal part of skin flora. The yeast has evolved to live on mammalian skin, so much so that it can't make fatty acids without the lipids—oils and fats—secreted by the skin.

Despite the abundance of Malassezia found on us, they remain understudied, Kowalski said.

"The skin is a parallel system to what's happening in the gut, which is really well-studied," she said. "We know that the intestinal microbiome can modify host compounds and make their own unique compounds that have new functions. Skin is lipid-rich, and the skin microbiome processes these lipids to also produce bioactive compounds. So what does this mean for skin health and diseases?"

Looking at human skin samples from healthy donors and experiments done with skin cells in the lab, Kowalski found that the fungal species Malassezia sympodialis transformed host lipids into antibacterial hydroxy fatty acids. Fatty acids have various functions in cells but are notably the building blocks for cell membranes.

The hydroxy fatty acids synthesized by Malassezia sympodialis were detergent-like, destroying the membranes of Staphylococcus aureus and causing its internal contents to leak away. The attack prevented the colonization of Staphylococcus aureus on the skin and ultimately killed the bacteria in as little as 15 minutes, Kowalski said.

But the fungus isn't a magic bullet. After enough exposure, the staph bacteria eventually become tolerant to the fungus, as they do when clinical antibiotics are overused.

Looking at their genetics, the researchers found that the bacteria evolved a mutation in the Rel gene, which activates the bacterial stress response. Similar mutations have been previously identified in patients with Staphylococcus aureus infections.

The findings show that a bacteria's host environment and interactions with other microbes can influence its susceptibility to antibiotics.

"There's growing interest in applying microbes as a therapeutic, such as adding bacteria to prevent the growth of a pathogen," Kowalski said. "But it can have consequences that we have not yet fully understood. Even though we know antibiotics lead to the evolution of resistance, it hasn't been considered when we think about the application of microbes as a therapeutic."

While the discovery adds a layer of complexity to drug discovery, Kowalski said she is excited about the potential of resident fungi as a new source for future antibiotics.

Identifying the antimicrobial fatty acids took three years and a cross-disciplinary effort. Kowalski collaborated with chemical microbiologists at McMaster University to track down the compound.

"It was like finding a needle in a haystack but with molecules you can't see," said Kowalski's adviser, Matthew Barber, an associate professor of biology in the College of Arts and Sciences at the UO.

Kowalski is working on a follow-up study that goes deeper into the genetic mechanisms that led to antibiotic tolerance. She is also preparing to launch her own lab to further investigate the overlooked role of the skin microbiome, parting from Barber's lab after bringing fungi into focus.

"Antibiotic-resistant bacterial infections are a major human health threat and one that in some ways is getting worse," Barber said. "We still have a lot of work to do in understanding the microorganisms, and also finding new ways that we can possibly treat or prevent those infections."