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Eighty percent of US antibiotics are used to promote the growth of livestock and poultry and protect animals from the bacterial consequences of the manure-laden environments in which they are grown. That's 34 million pounds a year of antibiotics from 2015.
Agricultural applications help generate drug resistance across multiple human bacterial infections, killing 23,000 to 100,000 Americans a year and, with a growing amount of antibiotics applied abroad, 700,000 people on a global scale.
Now a mushroom species, Candida auris, at developed MDT resistance and spreads rapidly across human populations around the world (see figure). The CDC reports 90% of C. auris infections are resistant to one antifungal and 30% to two or more.
C. auris, a Yeast, kills immunocompromised patients in hospitals, clinics and retirement homes at a tremendous pace, up to 40-60% of those who suffer from blood infections in a month.
In the rooms of infected and deceased people, the fungus appears uncompromising in almost all attempts at eradication. The mushroom can to survive even a spray of hydrogen peroxide aerosol from floor to ceiling.
How did drug-resistant fungi come to haunt the modern hospital and jeopardize sterile waste as evidenced 150 years ago?
It is becoming more and more obvious that C. aurisResistance, as well as that of many other species of fungi, is attributable to the massive application of fungicides by industrial agriculture. These chemicals come close to the molecular structures of antifungal medications.
Through cultures – wheat, banana, barley, apple, among many others – fungicides select resistant strains that reach hospitals where they also resist drugs administered to patients.
The path of yeast resistance
Matthew Fisher and his colleagues recently classified six main classes of fungicides, all rarely used in the US Midwest before 2007.
the azoles and morpholines target the ergosterol biosynthesis pathway, which generates the plasma membrane of the mushroom cells. the benzimidazole interfere with the mushrooms cytoskeleton, prevent assembly of the cell microtubules. the strobilurins and succinate dehydrogenase inhibitors take more physiological pathways, by inhibiting the electron transfer chain of mitochondrial respiration. the anilinopyrimidines appear to target mitochondrial signaling pathways.
Candida auris at evolved resistance to a series of azole antifungals, including fluconazole, with varying susceptibilities to other azoles, amphotericin B, and echinocandins. Azoles, used in both crop protection and medical parameters, are broad spectrum fungicides, annihilating a wide range of fungi rather than targeting a specific type.
How were fungi and fungicides on the ground?
C. auris, Tom Chiller, of the CDC, has probably circulated for a long time alone for thousands of years. makes assumptions, was isolated for the first time in humans from the auditory canal of a 70-year-old Japanese woman in a Tokyo hospital in 2009 (although one isolate from 1996 was later identified). Subsequent isolation revealed that the yeast was able to infect the blood.
In order to identify the source of the infection, an international team sequence resistant isolates collected from hospitals in Pakistan, India, South Africa and Venezuela, 2012-2015.
Against all odds, the team found divergent amino acid replacements associated with azole resistance among ERG11 single nucleotide polymorphisms – one among many these SNPs – in four geographical regions. They are not the same strain, indicating that each resistant phenotype has appeared independently.
In other words, the strains isolated by distance each other has developed unique solutions for the fungicides to which they have been exposed.
This could indicate molecular adaptations to different exposures. But this could also indicate that in response to such a broad exposure to fungicides in the field, each strain evolved his own unique solution to the problem.
Even though mushrooms do not do it transfer horizontally their genes at the same speed as the virus and bacteria, the migration of patients and fungi, the latter by agricultural trade, can help increase the diversity of fungicide resistance circulating in a given location.
A second team identified several genotypes of different international origins within the relatively limited United Kingdom limits. A third team, as shown by the map nearby, identified a similar mixture in American cases.
But it is unclear, except in cases related to a trip, if all cases come from strains from abroad. Without a fungal base in, for example, domestic farm workers, an endogenous source remains a possibility.
Distribution of Candida auris clades in the United States. (A) Peak phylogenetic tree of parsimony among clinical marker isolates from Colombia, India, Japan, Pakistan, South Korea, South Africa, Venezuela, and the United States in the USA. (B) The frequency of American clinical cases by clade. (C) The phylogeography of introduced clades. The solid lines indicate introductions associated with patients who are known to have received health care abroad.To add complexity, there are also multiple mechanisms by which resistance appears.
Dominique Sanglard resume Third: decrease in drug concentration in fungal cells, change in drug target and compensatory mechanisms that reduce drug toxicity. At the top of these, all three can be reached by a variety of genetic events. In addition to SNPs, insertions in the fungus genome, deletions and structural modifications, including gene copy or chromosome events.
A study found 51 genes related to the sensitivity of circulating strains of a Fusarium the rust had to propiconazole, a single class of triazole fungicide.
The path to such resistance can be complex, going beyond a simple antifungal.
In 2015, researchers found that the C. auris the genome hosts several genes for the Family of cassette transporters with ATP link, a major superfamily of facilitators (MFS). MFS transports a wide variety of substrates across cell membranes and has proven to be effective dispose large classes of drugs. It allows C. auris to survive an attack of antifungal drugs.
The team found that the C. auris The genome also encodes a large number of gene families that facilitate the virulence of fungi. C. auris adaptive forms biofilms that support antifungal resistance through a high density of cells, the presence of sterols on biofilm cells and effective use and growth of nutrients.
Other mushrooms, other hazards
Candida auris is hardly the only deadly fungus converging towards multidrug resistance. The neighboring map shows several overlapping species in plant and human resistance.
A fungus, Aspergillus fumigatus, can offer a conditional overview of C. auris present and future trajectories.
Azole antifungals, itraconazole, voriconazole and posaconazole have long been used to treat pulmonary asperillogosis, the infection caused by A. fumigatus. Mushrooms cause about 200,000 dead each year, resistance to antifungal medications has changed rapidly over the past decade.
Studies comparing long-term azole users and patients who are just starting to take the drug have shown that A. fumigatus prevalence in both groups, suggesting that resistance evolved into agriculture rather than medical parameters.
The researchers found biogeographic evidence suggesting multiple resistance to triazole A. fumigatus Strains in clinical and environmental settings share significant overlap. In the nearby figure, drug-resistant A. fumigatus found in the field (green) and in clinical trials (red) map together, demonstrating their coupling in Europe and Asia.
Other work recently found azole-resistant A. fumigatus related to the use of triazole fungicides in agricultural fields outside Bogotá, Colombia. The soils were sampled from a set of cultivated fields and A. fumigatus was grown on agar treated with itraconazole or voriconazole fungicides. In more than 25% of cases, A. fumigatus persisted despite the fungicidal treatment.
This is, because of agricultural practices, Aspergillus enter hospitals already adapted to the multitude of anti-fungal cocktails designed to limit their spread. The release of azoles to fight fungi in grapes, corn, stone fruits and a myriad of other crops has created the conditions necessary to speed up drug resistance in human patients.
Although detailed phylogenetic and biogeographical research remains to be conducted, a quick review of the existing distribution maps suggests similarities between Aspergillus fumigatus and his younger cohort (and suddenly more infamous) Candida auris. Strains share similar geographic distributions, occupying many of the areas described above for C. auris.
The role of industrial agriculture
With areas of overlapping cases of resistance to humans and crops Aspergillus fumigatus and the growing spectrum of a new azole-resistant fungus that is evolving at lightning speed in a clinical setting, it is hoped that the use of azole fungicide will be closely watched otherwise simply eliminated.
The dangers of continuing on this path of agricultural development are serious.
Medical and agricultural azole fungicides share similar modes of action. Thus, when resistance appears in one area, it is easily transferable to another. In agricultural and medical fungicides, phenyl group of chemical forms van der Waals contact with the active site of gene cyp51A.
Organic chemistry aside, the close similarities that the Chowdhary group describes in the near figure suggest that a mutation in Aspergillus fumigatus to prevent the link to the cyp51A gene in agriculture – in particular a modification of the Enzyme 14-α sterol demethylase – would likely confer resistance to the medical applications of stereochemically similar drugs.
Azole agricultural fungicides include a third of the total fungicide market. Twenty-five different forms of agricultural inhibitors of azole demethylation are used, against only three forms of authorized medical azoles.
It is therefore not surprising that by applying these fungicides on a landscape scale of millions of pounds per year, the medical use of triazole antifungals, using the same mode of action, would quickly become ineffective.
Instead of intervening in the interest of global public health to limit these long-standing problematic applications, government policy in recent years has favored the lucrative global expansion fungicide, favoring conditions conducive to drug-resistant virulent fungi.
In 2009, fungicides were applied on 30% of the corn, soybean and wheat acreage in the United States, totaling 80 million acres. Preventive use of soybean rust fungicides increased four-fold between 2002 and 2006, despite doubtful economic logic. Global sales continue to skyrocket, tripling almost since 2005, from $ 8 to $ 21 billion in 2017.
Fungicides have developed not only in sales, but also in geographical distribution.
On nearby maps we see tetraconazole, an agricultural triazole, which had moved from isolated use in the western plains to the late 1990s to massive application in the Central Valley, Upper Midwest and Southeastern California. boscalid, A fungicide used in fruit and vegetable crops has grown from ~ 0.15 to 0.6 million pounds from 2004 to 2016, an increase of 400%. It is now widely applied throughout the country.
From each new location, fungicides infiltrate into the local environment.
In 2012, scientists from the USGS studied 33 different fungicides used in potato production found at least one fungicide in 75% of the surface waters tested and 58% of the groundwater samples. With half-lives up to several months, azole fungicides can easily reach and persist aquatic environments by runoff and spray drift, becoming very mobile.
While climate change is fundamentally reshaping the United States, resulting in higher global temperatures and extreme oscillations between drought and heavy rainfall, fungi are predicted develop beyond their current limits while responding specifically to new climatic regimes. Aspergillus flavus, the producer of a carcinogenic aflatoxin which reduces maize yields and poisons humans, thrives in drought conditions and significant water deficits.
As the market is considered a stronger force of nature than climate or public health, in current agricultural production, the use of broad-spectrum fungicides is not expected to increase.
Agriculture as its own mushroom control
In response to drug-resistant bacteria and fungi, research institutes are calling for more reliable data on antibiotic use in agriculture and the potential economic costs of transitioning high application rates.
A 2016 British report, citing the overapplication of agricultural fungicides, recommended increased surveillance for the use of antibiotics as a whole and a regulatory scheme organized by WHO, FAO and the OIE, which would list among its tasks a list of antibiotics essential to prohibit the use of agriculture.
But in addition to collecting more information and asking what seems to be minimal regulation, what should you do?
Given the recent challenges in antibiotic and herbicide resistance, it seems likely that chemical companies and their farmer customers will continue development. new fungicides based on targeted molecular research, several drug cocktails, and resistance to modified genes.
Government agencies may impose more dubious biosecurity measures, which also favor xenophobic anxieties and are used to blame the workers for contamination, rather than attacking the systemic failures of industrial agriculture.
The combined motives of powerful medical and agricultural companies are almost certain to promote "solutions" that exacerbate an arms race between toxic drug applications and fungi resistance, to permeate more and more deadly chemicals into the body. environment, consolidate and privatize the agro-pharmaceutical sector.
There is another, however, paradigm based on evidence to react to the fungicidal collapse.
A quick review of agroecological examples suggests that a combination of disease modeling and cultural practices such as crop rotation and cover crops can significantly reduce the presence of fungal diseases and hence fungicide dependence.
In Central Valley, California, strawberry growers have been using fumigation soils with fungicides to control the incidence of Verticillium wither, pathogenic soil fungi, found that planting broccoli crops between rotations of strawberry crops greatly reduced levels of Verticillium.
Dating back several decades, similar results have been achieved in the diversification of rotation of potato crops.
Researchers in India – a country where drug resistance is A. fumigatus and C. aurishave both been found – have studied innovative approaches to fight against the mildew of the potato.
Potato crops often receive high doses of azole fungicides to control fungal pathogens such as late blight. Rather than dealing with fungicides, scientists applied silica to leaf tissue, concluding that the silica was absorbed and strengthening the cell walls of the potato against fungal invasion. Rates of disease infestation ranged from 2.8 to 7.9% in silica-based integrated management systems and from 49.4 to 66.7% in conventional fungicide-dependent systems.
In general, organic farming Supports mutualistic mushrooms to a much greater extent than conventional agriculture, thereby crowding out pathogenic strains. Crop rotation, legume incorporation, and soil aggregate cultivation are ecological niches for soil microbiota.
Reduce chemical fertilizers and limit tillage, two agro-ecological practices that offer major benefits in terms of pollution reduction and carbon storage, as well as select for beneficial strains of arbuscular mycorrhizal fungi that form mutual relationships with plant roots and can confer resistance to soil pathogens.
The integration of agricultural production into a broader matrix of uncultivated vegetation is also important for controlling fungal pathogens. Wild landscapes reduce the potential for adaptation of pathogen populations to crops and modeling suggests that contiguous strips of wild plots reduce the aggressiveness of pathogens on crops.
The laboratories of Ivette Perfecto and John Vandermeer did a good job, writing in depth here and summarized here, looking for ways in which ecological relationships – predation, mutualism, competition, etc. – in the food chain in which a crop is found can isolate damage caused by pests, including by their teams, rust mushrooms.
You can find everything you need to know about mushrooms in the book by Vandermeer student Douglas Jackson. thesis on the control of agro-ecological mushrooms in coffee.
Zachary Hajian-Forooshani (pictured), another student from the University of Michigan, followed research from the 1970s and found Mycodiplose Fly larvae feed on coffee rust, according to the Perfecto-Vandermeer team study in Mexico and Puerto Rico.
More than mining soil
All this work fits well with agroecological theory that, according to current demographic policies and trends, agricultural fields integrated into a nature conservation matrix are more likely than "land preservation" approaches to conserve natural resources while simultaneously supporting rural livelihoods and food production using few external inputs.
It shows an image of the ecological complexity in which the fungicide war is exactly the wrong tool.
Today, fungicides are used in a system where diseases develop from simplified landscapes, vast and uninterrupted genetically identical monocultures, rapid global warming and a growing trade. faster.
In a cruel irony, the application of fungicides exerts an evolutionary pressure on the pathogens for them to develop resistance. at the same time this industrial management provides the almost perfect conditions to promote and propagate these virulent mutations.
It only makes sense when we recognize that the agri-food sector sees nature as its the strongest competition.
En éliminant les écologies locales et le travail presque gratuit qu'elles offrent pour aider les agriculteurs à enrichir leurs sols, à nettoyer leur eau, à polliniser leurs plantes, à nourrir leur bétail et à lutter contre les parasites, notamment les champignons pathogènes, les plus grandes entreprises peuvent désormais vendre des produits équivalents à des produits dérivés. un marché capturé.
Le dommage causé est plus que agricole ou économique. C’est un plan d’entreprise poursuivi même au risque d’affaiblir notre capacité à nous reproduire socialement en tant que civilisation.
Les agriculteurs et les activistes de l'alimentation se sont plaints que l'agriculture industrielle représente un peu plus que nutrient and extraction de carbone. Les entreprises obligent les agriculteurs à cultiver si rapidement que la production extrait le carbone du sol sous forme de denrées alimentaires. En conséquence, la terre et l’eau sont polluées dans un tel oubli que la sécurité alimentaire ne peut pas être pris en compte.
Avec cette pollution, les expositions professionnelles, les flambées de virulence et d’étendue croissante, les maladies métaboliques telles que le diabète, la résistance aux antibiotiques et maintenant la menace croissante de résistance aux fongicides, l’extraction de carbone s’étend désormais à la corruption de la santé publique mondiale.
Une fois l’ordre du jour, des agricultures alternatives poursuivies et actualisées depuis longtemps par les petits exploitants du monde entier, et appuyées par une littérature scientifique croissante, offrent un moyen de sortir de ce piège.
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