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Published On December 5, 2019

BASIC RESEARCH

The Fungal Frontier

The drug-resistant Candida auris has taken up residence in U.S. hospitals. What will it take to fight back?

On November 13, 2019, the Centers for Disease Control and Prevention listed five drug-resistant infections that currently pose an “urgent threat.” One organism stood out: Candida auris, the only fungus on the list. Not only can some strains of C. auris withstand all current antifungal treatments, but it can also live for weeks on skin, bedrails and other surfaces, giving it an untrammeled ability to spread from one patient to another.

In the 10 years since it was discovered in the ear of a patient in Japan (auris is Latin for ear), C. auris has appeared in hospitals around the world, and as many as 60% of infected patients die. As of October 2019, the CDC had confirmed more than 830 C. auris infections in 13 U.S. states, with most cases in the New York City, New Jersey and Chicago areas. “The numbers are concerning,” says Michael Mansour, an infectious disease researcher at Massachusetts General Hospital. “There’s been a steady rise of cases. There’s been no plateau.”

Perhaps most worrying is the current state of antifungal research. Fungal infections have historically received scant attention from pharmaceutical companies, partly because infections tend to only occur in seriously ill people with weakened immune systems. Even if the patients survive their infection, they likely won’t take an antifungal treatment for very long, Mansour says. “There’s a lack of an appetite among the companies that develop these drugs,” he says. “They need to see a significant financial return on the millions of dollars they spend in development. We need to convince them that this is a worthwhile and valuable place to invest.”

There are some candidates in the pipeline. One is a novel antifungal oral drug, ibrexafungerp, in the works since 2005, according to Marco Taglietti, president of Scynexis, a biotech firm based in Jersey City, N.J. Scynexis’s drug—one of three now in clinical trials for treatment of C. auris—was originally developed as a treatment for fungal infections of Aspergillus and more common strains of Candida. It shows promise in an ongoing phase 3 clinical trial.

Fungi pose a special treatment challenge, according to Taglietti, because unlike “primitive” pathogens such as bacteria or viruses, their cellular structures and metabolic machinery closely resemble mammalian cells. Both fungal and mammalian cells have membranes around the cell nucleus, for example. Because of those similarities, it’s extremely challenging to find a treatment that kills the fungal infection without harming the patient. Taglietti notes that it took researchers a very long time to develop the three main classes of antifungal medications: azoles, polyenes and echinocandins. By comparison, there are dozens of classes of antibiotics for bacteria with hundreds of mechanisms of action.

The key to developing a new antifungal is finding the right target. The three drugs currently under investigation are ibrexafungerp, rezafungin and manogepix. Two of these work by targeting the fungi’s hard cell wall, a structure that doesn’t exist in mammalian cells and therefore has minimal risks of off-target effects, while the third inhibits the fungal enzyme Gwt1. All three show promise, but it will be a close race to see which one wins FDA approval first (if any), says Mahmoud Ghannoum, professor and director of the Center for Medical Mycology at Case Western Reserve University Hospitals Cleveland Medical Center who participated in a 2018 study of manogepix. “It’s an exciting time in mycology,” he says.

As researchers look for a magic bullet against C. auris, a troubling question remains: Where did C. auris come from, and how did it develop resistance so quickly? Other microbes gained their armor against antibiotics, at least in part, because they were exposed to them for decades in patients and “learned” to avoid them. But C. auris only recently, in 2009, started infecting humans.

Mansour and others suspect that C. auris has always lived in the environment, perhaps on plants or in the soil, and has evolved in response to the overuse of fungicides, such as fungus-killing sprays on crops. These could have prompted C. auris to evolve its own defenses to all current weapons.

In 2019, a paper in the journal mBio suggested that a warming climate may have helped C. aurissurvive and thrive in its natural habitat, facilitating the transition from an environmental fungus to a human pathogen. If that scenario is correct, Mansour suspects that other new species of fungi may soon make the leap to humans, a potentially grim scenario.

On a positive note, he believes that institutions will be better prepared to treat the next outbreak thanks to the research and innovation inspired by the emergence of C. auris. And researchers will also benefit from the advances that C. auris has inspired. “We have a lot of steps to go to eradicate C. auris,” he says. “But we’re in a safer place now, and we already have a better idea of what we need to do to avoid the next crisis.”