A Lethal Industrial Farm Fungus Is Spreading Among Us

Eighty percent of U.S. antibiotics are used to promote livestock and poultry growth and protect the animals from the bacterial consequences of the manure-laden environments in which they are grown. That’s 34 million pounds a year of antibiotics as of 2015.

The agricultural applications help generate drug resistance across multiple human bacterial infections, killing 23,000-100,000 Americans a year and, with an increasing amount of antibiotics applied abroad,700,000 people worldwide.

Now a fungal species, Candida auris, has developed multidrug resistanceand is rapidly spreading across human populations across the globe (see figure). The CDC reports 90% of C. auris infections are clocking in resistant to one antifungal drug and 30% to two or more.

C. auris, a yeast, is killing immunocompromised patients in hospitals, clinics, and nursing homes at a prodigious clip, up to 40-60% of those who suffer bloodstream infections in a month’s time.

In the rooms of the infected and the dead, the fungus appears intransigent to nearly all attempts at eradication. The fungus can surviveeven a floor-to-ceiling spray of aerosolized hydrogen peroxide.

How have drug-resistant fungi come to haunt the modern hospital and jeopardize the sterile spaces asepsis addressed 150 years ago?

It is becoming increasingly apparent that C. auris’s resistance, and that of many other fungi species, is traceable to industrial agriculture’s mass application of fungicides. These chemicals approximate the molecular structures of antifungal drugs.

Across crops — wheat, banana, barley, apple, among many others — the fungicides select for resistant strains that find their way into hospitals where they are also resistant to the drugs administered to patients.

The Path of Yeast Resistance
Matthew Fisher and colleagues recently classified six main classes of fungicides, all rarely used in the U.S. Midwest before 2007.

The azoles and morpholines target the ergosterol biosynthetic pathway,which generates the plasma membrane of fungi cells. The benzimidazolesinterfere with fungi cytoskeleton, preventing the assembly of cellmicrotubules. The strobilurins and succinate dehydrogenase inhibitors take more physiological routes, inhibiting the electron transfer chain of mitochondrial respiration. The anilinopyrimidines appear to target mitochondrial signalling pathways.

Candida auris has evolved resistance to a suite of azole antifungals, including fluconazole, with variable susceptibilities to other azoles,amphotericin B, and echinocandins. Azoles, used in both crop protection and medical settings, are broad-spectrum fungicides, annihilating a wide range of fungi rather than targeting a specific type.

How Did Fungus and Fungicide Find Each Other in the Field?
C. auris, likely long circulating on its own for thousands of years as CDC’s Tom Chiller hypothesizes, was first isolated in humans from the ear canal of 70-year old Japanese woman at a Tokyo hospital in 2009 (although a 1996 isolate was subsequently identified). Later isolation found the yeast capable of bloodstream infection.

In an effort to identify the source of the infection, an international teamsequenced resistant isolates collected from hospitals across Pakistan, India, South Africa, and Venezuela, 2012–2015.

Against expectations, the team found divergent amino acid replacements associated with azole resistance among the ERG11 single nucleotide polymorphisms — one among several such SNPs — across four geographic regions. They weren’t the same strain, indicating that each resistant phenotype had emerged independently.

  Serialisation – the future of food industry traceability

In other words, strains isolated by distance from each other evolved unique solutions to the fungicides to which they were exposed.

That might indicate molecular adaptations to different exposures. But it also might indicate that in response to such wide exposure to fungicides in the field, each strain evolved its own unique solution to the problem.

Even though fungi do not horizontally transfer their genes at rates that virus and bacteria do, migration of patients and fungi alike, the latter by way of agricultural trade, can help increase diversity in the fungicidal resistance circulating in any one locale.

A second team identified multiple genotypes of different international origins in the relatively bounded confines of the United Kingdom. A third team, as the nearby map shows, identified a similar mix in U.S. cases.

But it isn’t clear other than travel-related cases whether all the cases originated from strains from abroad. Without a baseline of fungal load among, say, domestic agricultural workers, an endogenous source remains a possibility.

Distribution of Candida auris clades in the United States. (A) Maximum parsimony phylogenetic tree of marker isolates from Colombia, India, Japan, Pakistan, South Korea, South Africa, Venezuela, and U.S. clinical cases in the USA. (B) The frequency of U.S. clinical cases by clade. (C) The phylogeography of introduced clades. Solid lines indicate introductions that are associated with patients known to have received health care abroad.

Dominique Sanglard summarizes three: decreases in drug concentration in fungal cells, alterations of the drug target, and compensatory mechanisms that depress drug toxicity. Atop these, the three can be arrived at by a variety of genetic events. Alongside SNPs are insertions into the fungus genome, deletions, and structural changes, including gene or chromosome copy events.

One study found 51 genes related to how sensitive circulating strains of aFusarium blight were to propiconazole, only a single class of triazole fungicide.

The road to such resistance can be complex, winding beyond merely evolving out from underneath an antifungal directly.

In 2015, researchers found that the C. auris genome hosts several genes for the ATP-binding cassette transporter family, a major facilitator superfamily (MFS). MFS transports a large variety of substrates across cell membranes and been shown to effectively dispose of broad classes of drugs. It permits C. auris to survive an onslaught of antifungal drugs.

The team found that that the C. auris genome also encodes a slew of gene families that facilitate the fungi’s virulence. C. auris adaptively formsbiofilms that support antifungal resistance by way of a high density of cells, the presence of sterols on biofilm cells, and efficient nutrient use and growth.

Candida auris is hardly the only deadly fungus converging upon multidrug resistance. The nearby map shows multiple species overlapping in plant and human resistance.

One fungus, Aspergillus fumigatus, may offer a conditional preview of C. auris’s trajectories present and future.

Azole antifungals itraconazole, voriconazole, and posaconazole have long been used to treat pulmonary asperillogosis, the infection caused byA. fumigatus. The fungi causes approximately 200,000 deaths per year, in the past decade rapidly developing resistance to antifungal drugs.