The path of yeast resistance

Candida
Public Domain Files
A fungus has developed multiple-drug resistance and is rapidly spreading across the globe.

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Candida auris is infiltrating hospitals, clinics and nursing homes and killing immunocompromised patients at a prodigious clip, up to 40-60 percent of those who suffer bloodstream infections.

The CDC reports that ninety percent of C. auris infections are clocking-in resistant to one antifungal drug and 30 percent to two or more. 

A report published by the Agroecology and Rural Economics Research Corps investigates how these drug-resistant fungi have come to haunt the modern hospital and jeopardize the sterile spaces that asepsis addressed 150 years ago. 

Drug resistance 

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

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. 

Eighty percent of US antibiotics are applied to promote livestock and poultry growth and protect the animals from the bacterial consequences of the manure-ladened environments in which they are grown. That’s a staggering 34 million lbs a year as of 2015. 

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, an estimated 700,000 people worldwide.

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

Candida auris has evolved resistance to a suite of azole antifungals, a type of  broad-spectrum fungicides that are used in both crop protection and medical settings and annihilate a wide range of fungi rather than targeting a specific type. 

Emerging independently

CDC’s Tom Chiller hypothesizes that C. auris has likely been circulating on its own for thousands of years. 

The fungus 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 team sequenced resistant isolates collected from hospitals across Pakistan, India, South Africa, and Venezuela from 2012–2015. 

Against expectations, the team found divergent amino acid replacements associated with azole resistance among the ERG11single nucleotide polymorphisms, one among several such SNPs, over four geographic regions. They weren’t the same strain, indicating that each resistant phenotype had emerged independently. 

Strains isolated by distance from each other evolved unique solutions to the fungicides to which they were exposed. This 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.  

Resistance evolution 

Even though fungi do not horizontally transfer their genes (or receive them) at rates that virus and bacteria do, the migration of patients and fungi alike - the latter by way of agricultural trade - can help increase local diversity in fungicidal resistance in the field. 

To add to the complexity, there also appear multiple mechanisms by which resistance emerges. 

Dominique Sanglard summarizes three: decreases in intracellular drug concentration, alterations of the drug target, and compensatory mechanisms that depress drug toxicity. 

On top of these, the three can be arrived upon by a variety of genetic events. Alongside SNPs are insertions into the genome, deletions, and structural changes, including gene or chromosome copy events. 

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

Resistance evolution in fungi can be quite elaborate. 

Other fungi 

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.

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

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

Azole antifungals itraconazole, voriconazole, and posaconazole have long been used to treat pulmonary asperillogosis, the infection caused by Aspergillus fumigatus. The fungi causes approximately 200,000 deaths per year. In the past decade, it has rapidly developed resistance to antifungal drugs. 

Antifungal cocktails

Studies comparing long-term azole drug users and patients just beginning to take azole have shown that drug-resistant Aspergillusfumigatus was prevalent in both groups, suggesting that resistance evolved in agricultural rather than medical settings.

Researchers recently found azole-resistant Aspergillus fumigatus related to the use of triazole fungicides in agricultural fields outside of Bogotá, Colombia. Soils were sampled from an array of crop fields and A. fumigatuswas grown on agar treated with itraconazole or voriconazole fungicides. 

In more than 25 percent of cases, despite the fungicide treatment, A. fumigatus persisted.

That is, due to agricultural practices, Aspergillus is entering hospitals already adapted to the slew of antifungal cocktails designed to check its spread. Dumping azoles to control for fungi on grapes, corn, stone fruit, and a myriad of other crops generated the conditions to accelerate drug resistance in human patients. 

While extensive phylogenetic and biogeographical research remains to be conducted, a quick perusal of existing distribution maps suggests geographic similarities between Aspergillus fumigatus and its younger (and now more infamous) cohort C. aurus.

Agricultural development 

With zones of overlapping human and crop resistant cases of Aspergillus fumigatus, the rising spectre of a new azole resistant fungi that is ravaging clinical settings and evolving at lightning speed, one would hope that azole fungicide use would be closely monitored if not phased out. 

The dangers of continuing upon this path of agricultural development are profound. 

Medical and agricultural azole fungicides share similar modes of action, so when resistance pops up in one arena it is easily transferable to another. 

Agricultural azole fungicides comprise a third of the total fungicide market. Twenty-five different forms of agricultural azole demethylation inhibitors are in use, compared to just three forms of licensed medical azoles.

We shouldn’t be surprised that in applying such fungicides at the landscape scale in the millions of pounds annually, the medical use of triazole antifungals, using the same mode of action, would rapidly turn ineffective. 

Preventative use

In 2009, fungicides were applied on 30 percent of corn, soybean, and wheat acreage in the US, totalling 80 million acres. 

Preventative use of fungicides to control soybean rust quadrupled between 2002 and 2006, despite dubious economic rationale. Global sales continue to skyrocket, nearly tripling since 2005, from $8 billion to $21 billion in 2017

Fungicides expanded not only in sales but also in geographic distribution.

Tetraconazole, an agricultural triazole, moved from isolated usage in the western Plains in the late 1990s to massive application throughout California’s Central Valley, the upper Midwest, and southeast. 

Boscalid, a popular fungicide used in fruit and vegetable crops, has increased from around 0.15 to 0.6 million pounds from 2004 to 2016, a 400 percent increase, and is now widely applied across the country.

From within each new locale, the fungicides percolate into the local environment.

In 2012, USGS scientists studied 33 different fungicides used in potato production and found at least one fungicide in 75 percent of tested surface waters and 58 percent of ground water samples. With half-lives stretching to several months, azole fungicides are able to easily reach and persist in aquatic environmentsthrough runoff and spray drift, becoming highly mobile.

Climate change 

As climate change fundamentally reshapes the US, bringing higher overall temperatures and extreme oscillations between drought and heavy rainfall, fungi are predicted to expand outside of their current ranges while also responding specifically to new climate regimes. 

With the market treated as a force of nature stronger than climate or public health, under current agricultural production, broad-spectrum fungicide use is likely to increase.

A 2016 UK report, citing agricultural overapplication of fungicides as a major issue, recommended increased surveillance of antibiotic usage overall and a regulatory apparatus orchestrated by the WHO, FAO, and OIE to create a list of critical antibiotics that should be disbarred from agriculture use. 

But aside from collecting more information, what is to be done?

Alternative solutions

Given recent travails in antibiotic and herbicide resistance, it seems likely that chemical companies and their farming clients will pursue developing new fungicides based on targeted molecular research, multiple drug cocktails, and gene-edited resistance

The conjoined motives of powerful medical and agricultural companies are almost certain to promote ‘solutions’ that exacerbate an arms race between toxic drug applications and fungal resistance, spew increasingly lethal chemicals into the environment, and further consolidate and privatize agricultural and medical technology sectors. 

But a quick review of agroecological examples suggests that a combination of disease modeling and cultural practices such as crop rotation and cover cropping can greatly reduced the presence of fungal diseases and thus dependence on fungicides. 

In the California’s Central Valley, strawberry producers accustomed to fumigating soils with fungicides to control incidence of Verticillium wilt, a pathogenic soil fungi, have found that planting broccoli crops in between rotations of strawberry crops greatly reduced levels of Verticillium. 

Similar results dating back several decades have been found in the diversification of potato crop rotations.

Ecological complexity

In general, organic farming supports mutualistic fungi to a much greater degree than conventional farming due to crop rotations, incorporation of legumes, and development of soil aggregates supporting ecological niches for soil microbiota. 

Reducing chemical fertilizers and limiting tillage, two agroecological practices with major benefits for reduced pollution and enhanced carbon storage, also select for beneficial strains of arbuscular mycorrhizal fungi which form mutualistic relationships with plant roots and can confer resistance to soil pathogens.

What emerges is a picture of ecological complexity in which fungicidal warfare would be exactly the wrong tool. 

Instead, fungicides are applied in a system in which diseases thrive out of landscape simplification, vast and uninterrupted genetically identical monocultures, rapidly accelerating global warming, and an ever quickening pace of global trade. 

In a cruel irony, fungicide application places evolutionary pressure on pathogens to develop resistance at the same time that industrial management provides the near-perfect conditions for fostering and spreading these virulent mutations.

Food activists

Farmers and food activists have complained industrial agriculture offers little more than nutrient and carbon mining.

Companies are compelling farmers to grow so much so fast that production squeezes carbon out of the soil in the form of food commodities. As a result, land and water are polluted into such oblivion that food safety cannot be accounted for.

By said pollution, occupational exposures, outbreaks of increasing virulence and extent, metabolic diseases such as diabetes, antibiotic resistance, and now the growing threat of fungicide resistance, carbon mining now extends to digging out global public health.

These Authors

Alex Liebman is a plant-soil and political ecologist writing and researching agri-food systems in U.S. and Colombia and lithium and copper extraction and indigenous territorial struggles in Chile. 

Rob Wallace is an evolutionary biologist, agroecologist, and public health phylogeographer.

This article is a modified version an in-depth report published by the Agroecology and Rural Economics Research CorpsRead the full version here.

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