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Genesis of azole antifungal resistance from agriculture to clinical settings Maria Manuel Azevedo, Isabel Faria-Ramos, Luísa Cruz, Cidália Pina-Vaz, and Acácio Gonçalves Rodrigues J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.5b02728 • Publication Date (Web): 19 Aug 2015 Downloaded from http://pubs.acs.org on August 25, 2015

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Journal of Agricultural and Food Chemistry

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Title. Genesis of azole antifungal resistance from agriculture to clinical settings

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Maria-Manuel Azevedo1,2,3, Isabel Faria-Ramos1,2, Luísa Costa Cruz1, Cidália Pina-

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Vaz1,2,4, Acácio Gonçalves Rodrigues1,2

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Portugal.

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Medicine, University of Porto, Porto, Portugal

Department of Microbiology, Faculty of Medicine, University of Porto, Porto,

Center for Research in Health Technologies and Information Systems, Faculty of

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School D. Maria II, Rua da Alegria, 4760-067, Vila Nova de Famalicão, Portugal.

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Department of Clinical Pathology, Centro Hospitalar de São João, Porto, Portugal.

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Corresponding author

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Maria Manuel Azevedo

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Department of Microbiology, Faculty of Medicine, University of Porto, Porto, Portugal.

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E-mail: [email protected]

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Telefone:+351936320962

ACS Paragon Plus Environment


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ABSTRACT

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Azole fungal resistance, is becoming a major public health problem in medicine in

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recent years. However, it was known in agriculture since several decades; the extensive

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use of these compounds results in contamination of air, plants and soil.

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The increasing frequency of life-threatening fungal infections and the increase of

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prophylactical use of azoles in high-risk patients, taken together with the evolutionary

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biology evidence that drug selection pressure is an important factor for the emergence

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and spread of drug resistance can result in a dramatic scenario.

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This study reviews the azole use in agricultural and in medical context and discusses

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the hypothetical link between its extensive use and the emergence of azole resistance

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among human fungal pathogens.

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KEYWORDS: antifungals, azoles, fungal resistance, Candida, Aspergillus fumigatus,

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Portuguese agriculture

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INTRODUCTION

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The use of plant protection products (PPP) may have considerable negative effects on

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the environment 1. The use of azole fungicides in agriculture started around mid-1960s;

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since then, such compounds have been used extensively 2. In the European Union half

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of the total land of cereals and grapevine is treated with azole fungicides. Notably, much

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smaller quantities of azoles are used in the United States for plant protection3.

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The azoles used in agriculture are generally sprayed every year over the cultured area in

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order to control mildews, rust and other diseases in cereals, ornamental plants,

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vegetables, fruits and vineyards. According to Matthews, the widespread use of these

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compounds results in contamination of air, plants and soil with a lot of small particles of

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fungicide4.

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The hypothetical risk that the massive use of azoles in agriculture could induce

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antifungal resistance among human pathogens started to be discussed several years ago.

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Agricultural azoles could stress fungal species either members of the endogenous

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saprophytic flora or exogenous to the human body. The imbalance of fungal ecology

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could thus upset the population of medically important fungi. Human pathogenic fungi

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may therefore persist and thrive5, and in this situation, health risks for human beings

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increase.

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In order to address this problem, in particular regarding the Portuguese situation

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relatively to azole use in agriculture, this review was organized according the following

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topics: 1. Use of azole fungicides in agriculture; 2. Use of agricultural azole fungicides

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in Portugal; 3. Mode of action of drugs; 4. Hypothetical link between azole use in

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agriculture and human health; 5. Portuguese National Strategie plan for a sustainable

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use of plant protection products.

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Use of azole fungicides in agriculture

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The growing request for food in quantity/quality has placed a drastic pressure on the

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productive sector, often at the expense of the natural elements, with progressive

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reduction or elimination of pristine landscape. The use of PPP in this context may have

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strong negative effects on the environment, especially with regard to the possible

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contamination of surface water and groundwater. Azole compounds are PPP which are

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also used for preservation of materials, such as paints, coatings, wall paper paste, and

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are routinely applied to mattresses in order to prevent fungal growth. The most

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commonly compounds used in the European Union are imidazoles6 (Figure 1A)7 and

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triazoles (Figure 1B)8. They are widely used in preharvest phase, in grain-growing and

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grass-growing environments, as well as at postharvest phase to prevent fungal spoilage9

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by yeasts like Candida spp., Cryptococcus spp, Rhodotorula spp., Trichosporon

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penicillatum, Saccharomyces cerevisiae or filamentous moulds like Alternaria spp.,

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Aspergillus spp., Fusarium spp., Geotrichum spp10,11. In addition, they are also applied

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to treat plant infection when it becomes apparent.

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According to the manufacturer’s instructions, doses of 100g/ha should be used,

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corresponding approximately to 10 mg of azoles applied to 1 m2 of plant surface5. Data

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from the literature reveals that annually nearly 50% of the total acreage under cereal and

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grapevine production in Europe is treated with azole fungicides12. Comparatively, in the

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United States, less than 5% of the total crop area is treated with these compounds. In the

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European Union, the situation of the Netherlands stands out in particular, since the

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utilization of azole fungicides has almost doubled since the mid-1990s13. Several

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reasons are usually forwarded to justify the use of azoles in agriculture, in particular, the

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fact that these compounds are not expensive and that they exhibit broad spectrum

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activity. However, since azoles are very stable molecules, they can persist active in the


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soil and water during several months14 as well as in several fruits and vegetables15,16,17.

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Although the azole residues detected in many samples do not reach health hazards toxic

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levels, the amount could vary considerably. Data from the literature shows that

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considerable quantities of azole residues could persist in some food products during

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long time5.

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Farmers have been strongly encouraged to follow guidelines aiming to reduce the

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probability of developing resistance to agricultural antifungals and/or to minimise its

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extent and/or to increase the chance that any developed resistance would still be

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reversible. Such practices include the rotating use of antifungal products with different

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modes of action, as well as the preferential practice of a limited number of interventions

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using higher dosages as opposed to more frequent applications with lower dosages. This

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does not, however, imply that the use of antifungal substances in agriculture should not

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be closely monitored, considering the risk of accumulation of azoles in the soils (the

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half-life time of azoles is usually longer than 1 year), and because the newer compounds

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may be also at the origin of resistance development.

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Use of agricultural azole fungicides in Portugal

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In the particular case of Portugal, there is a real need to promote agriculture and invest

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in training farmers. According to the results of the Agricultural Census report18, the

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social characterization of the Portuguese family farm population consists of 793 000

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individuals representing, 7% of the resident population. The rural population aged

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considerably between 1999 and 2009; the average age increased from 46 to 52 years.

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The educational level is rather low; 40 % of subjects only attended the 1st cycle and

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22% have no schooling. However, despite these social indicators, significant

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improvements were registered during the ten year period under study; illiteracy rate

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decreased by 7% and the frequency of senior secondary cycle and higher education



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increased by 3%. At the present, the typical profile of the Portuguese farmer nowadays

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is a 63 year old male, having just completed the 1st cycle of basic education, only

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having practical agricultural training and working in agricultural activities about 22

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hours per week.

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By December 31, 2012, 907 PPP, based on 248 active substances were available in

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Portugal19. The largest volume of these substances available at the national market

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belong to the fungicides group, followed by herbicides and insecticides, representing the

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remaining products about 15% of the total PPP marketed. According to the Agricultural

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Statistics report the ratio between sales of PPP/agricultural area used was in 2008, 2009,

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2010 of 4.6, 3.8 and 3.8, respectively. In case the total sales volume is subtracted with

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the value of sulfur and derivates, this ratio corresponds to values of 1.9, 2.0, and 1.9,

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respectively19.

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Sales figures of PPP at national level constitute an indicator that can provide an

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estimation about the use of such products in Portugal. The amount of PPP sold in

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Portugal during 2012 corresponded to a total of 12 462237 kg, expressed as active

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substances. The fungicides contributed with about 68.3% of the total of active

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substances sold, whereas sulphur represented 49.8 % of the total sales and 71.4% of all

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the fungicides sold. Figure 2 depicts an overview of fungicide sales by chemical group

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in Portugal between 2002 and 2012. Overall, a decrease in fungicide sales was

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registered from 2008 until 201220 . In respect to azoles, a consecutive decrease in sales

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was registered between 2002 and 2005; however, after 2006 the values started to

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increase again, reaching a peak in 2012 (Figure 3)20.

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Mode of action of azole drugs

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Concerning the mode of action, all the azole drugs interact and target the same active

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site in fungal enzyme; thus agricultural azole fungicides share the mode of action with


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medical azoles21. This results in a fungistatic rather than fungicidal effect; in this sense

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the terminology often used in agriculture “fungicides” is ambiguous.

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This class of compounds are sterol demethylation-inhibitors (SBIs) and impair the

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synthesis of ergosterol5,21. Azole drugs interfere with the activity of fungal lanosterol 14

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alpha-demethylase, an enzyme responsible for the transformation of lanosterol in

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ergosterol. Ergosterol is an important compound of the fungal cytoplasmatic membrane;

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the impairment of its metabolism induces cell membrane disorganization and decrease

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of fungal growth. Moreover, fungal growth arrest can also result from the accumulation

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of toxic ergosterol precursors22.

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The available SBIs-fungicides can be classified into four classes according to their

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respective target sites, which are membrane bound enzymes, namely: thiocarbamates or

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allylamines (squalene epoxidase), inhibithors of C14-demethylation or DMIs, Amines

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(∆14 reduction or ∆8-> ∆7 – isomerization) and hydroxyanilides (C4-demethylation).

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However, several resistance mechanisms to SBIs have been described. The two major

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involve either alterations of the target enzyme, which result in a reduced affinity to

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fungicides or a decrease of the intracellular drug accumulation, that is linked to an over

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expression of membrane transporter proteins, usually namely effux-pumps.

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Hypothetical link between azole use in agriculture and human health

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Several reports claim that antibiotic resistance can be a natural occurrence in the soil. In

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fact, microorganisms inhabiting soil have to strive for energy sources; it is known that,

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some bacteria and fungi develop the ability to produce antibiotic compounds in order to

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destroy their competitors. Such microorganisms are thus naturally immune to the effects

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of their own excretions23.

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The development of resistance to azoles among plant fungal pathogens is complex and

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generally progressing in small steps. First descriptions date from long time ago and



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claim that some plant pathogens acquired azole resistance following agricultural

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exposure24. Data from the literature describes resistance or tolerance to triazole

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fungicides for pathogens of crops such as wheat, barley and strawberry25. While in

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Portugal resistance to triazoles in vineyard powdery mildew has been detected in the

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past26, still recent studies describe this situation27.

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Over the last two decades, clinically important fungal infections have become more

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prevalent because medical progress allows the survival of an increasing number of

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immunocompromised patients. However, resistance to antifungal drugs also became a

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critical medical problem.

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It has been proposed, that there may be a direct relation between the development of

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resistance to azole fungicides used in agricultural practice and the development of

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resistance to azole antifungals observed in clinical settings28. Exposure of a

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microorganism to any antibiotic involves a risk of emergence of resistance through the

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process of selection. The knowledge about the rate and extent of the emergence of

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resistant organisms29 and whether this resistance is reversible or not, is a very relevant

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issue to clinical medicine. Resistance depends upon a variety of factors and conditions,

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including: the mechanisms of action of the compound; the target site(s) in the organism

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and their number; the risk of resistance transference between individual organisms and

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species; and the mechanism of such resistance.

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Resistance in fungi and the mechanisms involved in its development and transmission

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differ in some extent from those seen in bacteria. There is no evidence that the genes

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that confer resistance to fungi can be transferred horizontally, a key difference with

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bacteria. There are two forms of resistance, primary (or intrinsic) and secondary. In

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primary resistance, the fungal organism cannot be inhibited even by high concentrations

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of an antifungal drug. For example, Aspergillus fumigatus is intrinsically resistant to


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fluconazole and does not respond at all to this drug. Similarly, Candida krusei and C.

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glabrata isolates are often intrinsically resistant to fluconazole. Conversely, fluconazole

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resistance in Candida albicans can emerge de novo during prolonged treatment; which

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is an example of secondary resistance30.

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There are at least three different mechanisms by which antifungal drug resistance might

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arise. They can involve increased efflux of drug, altered target demethylase sites and the

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availability of alternative pathways for the synthesis of cell membrane sterols. Candida

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krusei shows intrinsic resistance to fluconazole largely due to the last mentioned

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mechanism.

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There is also evidence that in clinical settings the adoption of some therapeutic

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strategies to treat patients over long periods or to prevent infection through antifungal

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prophylaxis can result in selection of resistant organisms, either of the same or of

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different species. Several studies have shown that a strong and persistent antimicrobial

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pressure upon a microbial population will undoubtedly lead to the selection of resistant

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clones, particularly whenever the antimicrobial agent induces a static effect instead of a

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biocidal effect23. This situation can happen in fungi submitted to azole pressure. Since

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azoles represent first line clinical antifungals, the topic of azole resistance is of great

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medical relevance. Azole resistance can thus hypothetically result from exposure to

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azole compounds, which can happen in vivo (azole treated patients) or due to the

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presence of these compounds in the environment, namely agriculture use31. The massive

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use of azoles in agriculture could stress susceptible species of the fungal flora, both in

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nature but also at human endogenous niches. This disturbance in the fungal flora

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ecology could result in changes among the population of medically important fungi;

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human fungi pathogenic may thus persist and thrive 5. In this situation, health risks

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might increase seriously. In addition, new resistance mutations could also develop in



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the environment. Studies addressing the epidemiology of invasive fungal infections are

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of high relevance in order to determine the hipothetical impact of anthropogenic

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activities upon the susceptibility profile of yeast and filamentous fungi and also to

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report any emergent species. In Portugal, two studies conducted at the same institution,

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within a ten year interval, revealed several relevant differences not only in susceptibility

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patterns but, most importantly, regarding species distribution29,32.

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Invasive aspergillosis is a very dangerous opportunistic fungal infection. The conidia of

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Aspergillus spp. usually become airborne from soil or decaying organic matter and

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patients become infected usually by inhalation from such a reservoir13. In 2009,

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Snelders and co-workers provided for the first time evidence that patients with invasive

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aspergillosis due to azole resistant A. fumigatus might have acquired the organism from

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the environment31. According to this study, resistant strains of A. fumigatus to medical

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azoles were found in the soil and compost from areas nearby to the admission hospital31.

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The dominance of a single resistance mechanism and the genetic homology between the

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clinical and environmental isolates suggested that the acquisition of azole-resistant

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isolates from the environment was the most important infection route.

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Azole resistance among A. fumigatus isolates was not only found in Dutch hospitals33;

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resistant isolates were also detected in several European countries such as in Spain34,

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Belgium35, Denmark36 , Sweden37 and France38.

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Human and animal fungal pathogens such as Coccidioides, Histoplasma, Aspergillus

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and Cryptococcus do also thrive in the environment, including plants and food products.

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It should also be stressed that only a few yeast species are endogenous to the flora of

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healthy human beings; in most occasions, the fungal pathogens are taken up from the

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environment. Thus, environmental resistant isolates could have developed antifungal

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resistance following a prolonged environmental selective azole pressure. Therefore, the


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probability that an individual might be exposed to an environmental resistant fungal

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organisms is real and high. Nevertheless, the stress of residual azoles that might be

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present in vegetables and other food products upon the endogenous native fungal flora

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of humans should not be neglected and may also contribute to the emergence of

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antifungal resistance at endogenous niches.

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In the case of A. fumigatus, it was concluded that two distinct models of resistance

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might have developed. One of them occurs following long time-exposure to azole

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treatment, as might occur in clinical settings, supported by several possible genetic

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mutations, the other model is facilitated by a single mechanism, TR/L98H mutation,

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that occurs in environmental isolates under the selective pressure of agricultural azole

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fungicides. This kind of mutation started spreading worldwide and has nowadays also

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been described outside Europe39. A very recent study conducted in France describes a

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clinical case of a French farmer who developed invasive aspergillosis caused by an

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azole-resistant A. fumigatus with the TR34/L98H mutation following hematopoietic

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stem cell transplantation40. This farmer had worked in fungicide-sprayed fields from

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where A. fumigatus TR34/L98H isolates were also recovered. This study supports the

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assumption that humans might indeed be infected with environmental azole resistant

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isolates.

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Measures in order to control this problem should be adopted, in particular in the

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Netherlands, where the TR/L98H mutation became endemic5. Interestingly, in Portugal,

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back in 2007 Araújo et al.41 compared the antifungal susceptibility profile of different

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Aspergillus species recovered from environmental and clinical sources and found high

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MIC levels of clinical antifungals among environmental strains.

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Verweij and co-workers reported cross-resistance between azole drugs, which

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constitutes a very relevant clinical issue, with relatively few therapeutic options



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available in the case of invasive Aspergillus infections42 . More recently, several studies

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demonstrated the development cross resistance between agricultural and medical

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azoles13,21. Faria-Ramos and co-workers,43 clearly demonstrated that exposure of

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clinically relevant moulds and yeast organisms to azoles used in agriculture does result

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in the emergence of cross-resistance to clinical azoles, which may not be reversible.

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Additional research efforts aiming to reduce the emergence of fungicide resistance are

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urgently needed, both in agriculture and in medical settings. Since the mechanisms

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providing the basis for fungicide resistance are likely to be conserved between plant and

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human pathogens, plant pathologists and medical microbiologists should develop

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effective strategies counteracting the development of antifungal resistance, in a

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concerted action.

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Portuguese National Strategie Plan for a sustainable use of plant protection

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products

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The Directive No. 2009/128/EC is an innovation in the context of the Community

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legislation about PPP; for the first time legislation was provided about the use of PPP,

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in order to protect human health and the environment from possible risks inherent to its

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use.

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In order to operationalize the implementation of this Directive at national level, the law

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nº. 26/2013 was published; it regulates the distribution, sales and application of PPP by

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professional users as well as adjuvants for PPP; it also sets the monitoring procedures

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for the use of PPP. Together with the Law nº. 86/2010 (which establishes a mandatory

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inspection scheme of PPP and its application using equipment authorized for

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professional use) constitutes the transposition into national legal order of that

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Community law.


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The article 51º of this law envisaged the creation of National Action Plans. These plans

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aimed at reducing the risks and effects of the use of PPP on human health and upon the

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environment, and to promote the development of integrated protection technical

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alternatives to reduce dependence of the use of conventional PPP.

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The Portuguese National Plan has been prepared with the collaboration of various

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agents, either from public or private sector, without which would not have been possible

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to achieve the intended goals. It must also be pointed out that the implementation of this

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plan will only be effective with the committed collaboration of all the agents involved

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in manufacture, storage, sale and use of PPP, as well as those responsible for managing

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the effects and risks associated with the use of PPP. The correct application of PPP can

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be encouraged by the training of professionals, appropriate counselling at the point of

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sale, and monitoring/supervision of compliance by professional users. In the act of sale,

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adequate information about the use of PPP and the risks and safety instructions

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regarding human health, should be provided to buyers, in order to enable the adequate

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management of the risks inherent to the products concerned.

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The protection of professionals configures primarily a matter of safety and health

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regarding to the professional handling field use and application of pesticides. Risks may

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include not only acute intoxication, but also chronic and sub-chronic risks, resulting

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from prolonged exposure. The lines of action chosen for this intervention area are: i)

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Protection of professional users (commercial and storage settings); ii) Reduction of

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exposure; iii) Limitation of the use of certain PPP44.

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The main measure of protection regarding non-professional users is restricting its access

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to a limited category of PPP. In any case, buyers should be provided awareness of the

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risks associated with PPP use and about promotion of good general practices regarding

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its use.



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In order to assess the progress made in reducing the risks and adverse effects of the use

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of PPP, both to human health and the environment, monitoring plans should be in place

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so that, based on a sample of professional users and predefined criteria, it will be

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possible to assess the progresses resulting from the implementation of the general

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principles of integrated protection.

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In addition, is should be emphasized the relevance of the contribution of scientific

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research and field application of the most recently available scientific and technological

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information in improving resources and instruments available to the professional users,

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including complementary or alternative means of use of PPP.

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In conclusion, fungicide-based plant protection is at present indispensable for efficient

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and large-scale crop production. Notably, modern fungicides should exhibit negligible

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acute toxicity, and the regulations for fungicide application should ensure the

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availability of safe food. As long time periods and enormous financial investments are

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required to develop new fungicides, serious efforts must be taken in order to prevent

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emergence of fungicide resistance. This is particularly important since fungicides with

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novel modes of action are rarely found, and resistance to single-target fungicides may

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occur within the first few years of its field use.

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The key to prevent or at least delay the onset of development of fungicide resistance in

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agriculture is the preparation of efficient fungicide mixtures as well as the rotation

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between fungicides with different modes of action during a crop campaign. The

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recommendations are to maintain highly efficient fungicides in the market, precluding

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the use of monofungicides, in order to keep its use above a threshold allowing

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quantitative resistance to develop. The strategy adopted during the last decades was to

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apply single-target fungicides, resulted in a strong selective pressure for mutants with a

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modified fungicide-binding site. As fungicides with more than one target are not easy to


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be overcome by mutations, the focus in fungicide screening should also be directed

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towards identifying multi-site inhibitors. After having such fungicides available, the risk

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of rapid occurrence of qualitative resistance might be strongly and effectively reduced.

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Nevertheless, particular attention should be devoted to the assessment of development

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of cross-resistance to clinical antifungals; strict monitoring of the emergence of fungal

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strains with resistance mechanisms, as well as variations in species distribution

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regarding both plant and human pathogens should be implemented.

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CONFLITCTS OF INTEREST

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The authors declare no conflict of interest.

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ACKNOWLEDGMENTS

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I. Faria-Ramos is supported by an FCT PhD grant (SFRH/BD/91155/2012).

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_pt.pdf).

-Volume

518 519 520 521 522


I


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22 523

LEGENDS

524

Figure 1. Chemical struture of imidazole (A), 1,2,4-triazole (B), fluconazole (C) and

525

tebuconazole (D).

526 527

Figure 2. Sales of fungicides in Portugal between 2002 and 2012 (Source: DGADR –

528

Direção Geral de Agricultura e Desenvolvimento Rural “Vendas de Produtos

529

Fitofarmacêuticos em Portugal 2002-2012” http://www.dgadr.mamaot.pt/).

530 531

Figure 3. Sales of agricultural azole in Portugal between 2002 and 2012 (Source:

532

DGADR – Direção Geral de Agricultura e Desenvolvimento Rural “Vendas de Produtos

533

Fitofarmacêuticos em Portugal 2002-2012” http://www.dgadr.mamaot.pt/).

534 535 536 537 538 539 540 541 542 543 544 545 546 547


Page 23 of 28


23 548 549 550

Figure 1

A

B

C

D

551 552 553

Figure 2

Sales of azoles for plant protection in Portugal (kg of active substance)

554

60000 50000 40000 30000 20000 10000 0 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 Years

555 556 557 558 559 560 561 562 563 564

Figure 3



Page 24 of 28

Sales of fungicides for plant protection in Portugal (kg of active substance)

24

14000000 12000000 10000000 8000000 6000000 4000000 2000000 0 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 Years

565


Page 25 of 28


208x172mm (150 x 150 DPI)



Figure 1. Chemical struture of imidazole (A), 1,2,4-triazole (B), fluconazole (C) and tebuconazole (D). 254x190mm (96 x 96 DPI)


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Page 27 of 28


254x190mm (96 x 96 DPI)



254x190mm (96 x 96 DPI)


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Genesis of Azole Antifungal Resistance from ... - ACS Publications

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