Is the emergence of fungal resistance to medical triazoles related to their use in the agroecosystems? A mini review

Aícha Daniela Ribas e Ribas Pierri Spolti Emerson Medeiros Del Ponte Katarzyna Zawada Donato Henri Schrekker Alexandre Meneghello Fuentefria About the authors

Abstract

Triazole fungicides are used broadly for the control of infectious diseases of both humans and plants. The surge in resistance to triazoles among pathogenic populations is an emergent issue both in agriculture and medicine. The non-rational use of fungicides with site-specific modes of action, such as the triazoles, may increase the risk of antifungal resistance development. In the medical field, the surge of resistant fungal isolates has been related to the intensive and recurrent therapeutic use of a limited number of triazoles for the treatment and prophylaxis of many mycoses. Similarities in the mode of action of triazole fungicides used in these two fields may lead to cross-resistance, thus expanding the spectrum of resistance to multiple fungicides and contributing to the perpetuation of resistant strains in the environment. The emergence of fungicide-resistant isolates of human pathogens has been related to the exposure to fungicides used in agroecosystems. Examples include species of cosmopolitan occurrence, such as Fusarium and Aspergillus, which cause diseases in both plants and humans. This review summarizes the information about the most important triazole fungicides that are largely used in human clinical therapy and agriculture. We aim to discuss the issues related to fungicide resistance and the recommended strategies for preventing the emergence of triazole-resistant fungal populations capable of spreading across environments.

Keywords:
Cross-resistance; Emerging fungal pathogens; Fungicide sensitivity; Agriculture; Medicine

Introduction

Fungicides are a key component in human therapy and the control of plant diseases caused by fungi that threaten human health and crop production.11 Horsfall JG. Fungi and fungicides. The story of a nonconformist. Annu Rev Phytopathol. 1975;13:1-14.

2 Hof H. Critical annotations to the use of azole antifungals for plant protection. Antimicrob Agents Chemother. 2001;45:2987-2990.

3 Russel PE. A century of fungicide evolution. J Agric Sci. 2005;143:11-25.

4 Dehne HW, Deising HB, Gisi U, Kuck KH, Russell PE, Lyr H. Modern. Fungicides and antifungal compounds. In: International Reinhardsbrunn Symposium Friedrichroda, Vol. 15.2007:45–51.
-55 Salam KP, Tomas JG, Beard C, Loughman R, Mac Leod WJ, Salam MU. Application of meta-analysis in plant pathology: a case study examining the impact of fungicides on wheat yield loss from the yellow spot-septoria nodorum blotch disease complex in Western Australia. Food Secur. 2013;5:319-325. Among the several types of fungicides, the azole group (triazole and imidazole derivatives) was first introduced in the 1970s.33 Russel PE. A century of fungicide evolution. J Agric Sci. 2005;143:11-25. Since then, azoles, especially the triazoles, have been widely used for the control of fungal diseases of several plants and human mycoses.66 Snelders E, Huis In't Veld RA, Rijs AJ, Kema GH, Melchers WJ, Verweij PE. Possible environmental origin of resistance of Aspergillus fumigatus to medical triazoles. Appl Environ Microbiol. 2009;75:4053-4057.

7 Brown GD, Denning DW, Levitz SM. Tackling human fungal infections. Science. 2012;336:647.
-88 Cools HJ, Fraaije BA. Update on mechanisms of azole resistance in Mycosphaerella graminicola and implications for future control. Pest Manage Sci. 2013;69:150-155. As opposed to other systemic fungicides, the specific site of action of triazoles is an inherent advantage that has led to improved control efficacy of the target fungus.99 Ma Z, Michailides TJ. Advances in understanding molecular mechanisms of fungicide resistance and molecular detection of resistant genotypes in phytopathogenic fungi. Crop Prot. 2005;24:853-863.,1010 Deising HB, Reimann S, Pascholati SF. Mechanisms and significance of fungicide resistance. Braz J Microbiol. 2008;39:286-295. However, experience has shown that these compounds are prone to resistance in the pathogenic population, especially without the following of recommended practices that are aimed at prolonging the effectiveness of these fungicides.99 Ma Z, Michailides TJ. Advances in understanding molecular mechanisms of fungicide resistance and molecular detection of resistant genotypes in phytopathogenic fungi. Crop Prot. 2005;24:853-863.,1111 McGrath MT. Fungicide resistance in cucurbit powdery mildew: experiences and challenges. Plant Dis. 2001;85:237-245.,1212 Denning DW, Park S, Lass-Florl C, et al. High-frequency triazole resistance found in nonculturable Aspergillus fumigatus from lungs of patients with chronic fungal disease. Clin Infect Dis. 2011;52:1123-1129.

In this context, the efficacy of triazole fungicides can be affected due to cross-resistance or when an isolate develops resistance to all fungicides in a chemical group.1313 Snelders E, van der Lee HA, Kuijpers J, Rijs AJMM, Varga J. Emergence of azole resistance in Aspergillus fumigatus and spread of a single resistance mechanism. PLOS Med. 2008;5:1629-1637.,1414 Snelders E, Camps SM, Karawajczyk A, et al. Triazole fungicides can induce cross-resistance to medical triazoles in Aspergillus fumigatus. PLoS ONE. 2012;7:e31801. Some authors have also suggested that cross- and multidrug-resistance may be driving forces in the development of resistance in fungi that are at the interfaces of agroecosystem, domestic, and hospital environments.1515 Bowyer P, Denning DW. Environmental fungicides and triazole resistance in Aspergillus. Pest Manage Sci. 2013;70:173-178.,1616 Lelièvre L, Groh M, Angebault C, Maherault AC, Didier E, Bougnoux ME. Azole resistant Aspergillus fumigatus: an emerging problem. Med Mal Infect. 2013;43:139-145. For instance, emerging fungi in clinical environments include saprophytic or plant pathogenic fungi that have previously exposed to triazole fungicides and end up spreading into the environment and infecting humans.66 Snelders E, Huis In't Veld RA, Rijs AJ, Kema GH, Melchers WJ, Verweij PE. Possible environmental origin of resistance of Aspergillus fumigatus to medical triazoles. Appl Environ Microbiol. 2009;75:4053-4057.,1717 Mehl HL, Epstein L. Fusarium solani species complex isolates conspecific with F. solani f. s: cucurbitae race 2 from naturally infected human and plant tissue and environmental sources are equally virulent on plants, grow at 37 °C and are interfertile. Environ Microbiol. 2007;9:2189-2199.

18 De Lucca AJ. Harmful fungi in both Agriculture and Medicine. Rev Iberoam Micol. 2007;24:3-13.
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In this mini review, we summarize key aspects of the triazoles for therapeutic use and discuss the possible link between triazole-resistant clinical isolates and the widespread use of triazole fungicides for the control of fungal diseases, which would have a major impact in agriculture.

Basic aspects and therapeutic use of triazoles

The azole fungicides are of synthetic origin and are characterized by the presence of an aromatic five-membered heterocycle. These include triazoles (two carbon atoms and three nitrogen atoms), imidazoles (three carbon atoms and two nitrogen atoms), and thiazoles (three carbon atoms, one nitrogen atom and one sulfur atom).2020 Catalán M, Montejo JC. Antifúngicos sistêmicos. Farmacodinâmica Y Farmacocinética. Rev Iberoam Micol. 2006;23:39-49. The characteristics of the azole rings, which are distinguished by the number of nitrogen and sulfur atoms, change the physical and chemical properties, toxicity, and therapeutic efficacies of these compounds.2121 Sheppard D, Lampires HW. Agentes antifúngicos. In: Katzung BG, ed. Farmacologia Básica e Cínica. Rio de Janeiro, Brazil: McGraw Hill Interamericana do Brasil, Guanabara Koogan; 2008:707–714. Therefore, the addition of different substitutes to the pristine 1,2,4-triazole molecule influences its fungicide or fungistatic effect.

Triazoles affect the biosynthesis of ergosterol, a fundamental component of the fungal cell plasma membrane.2222 Brent KJ. Fungicide Resistance in Crop Pathogens, How Can it be Managed. Brussels: Global Crop Protection Federation; 1995. The main target of antifungal azole drugs is lanosterol 14-α demethylase (Erg11 protein), a cytochrome P450 enzyme that is involved in the conversion of lanosterol to 4,4-dimethylcholesta-8(9),14,24-trien-3β-ol. The azole agents link to this enzyme using the aromatic five-membered heterocycle and thereby inhibit the cytochrome P450 catalytic activity.99 Ma Z, Michailides TJ. Advances in understanding molecular mechanisms of fungicide resistance and molecular detection of resistant genotypes in phytopathogenic fungi. Crop Prot. 2005;24:853-863.,2323 Becher R, Wirsel SGR. Fungal cytochrome P450 sterol 14α-demethylase (CYP51) and azole resistance in plant and human pathogens. Appl Microbiol Biotechnol. 2012;95:825-840. The absence of ergosterol and the increase of intermediate compounds alter fungal membrane integrity as well as cell morphology, which inhibits fungal growth.2424 Becher R, Hettwer U, Karlovsky P, Deising HB, Wirsel SGR. Adaptation of Fusarium graminearum to tebuconazole yielded descendants diverging for levels of fitness, fungicide resistance, virulence, and mycotoxin production. Phytopathology. 2010;100:444-453.,2525 Serfling S, Ordon F. Virulence and toxin synthesis of an azole insensitive Fusarium culmorum strain in wheat cultivars with different levels of resistance to Fusarium head blight (FHB). Plant Pathol. 2014;63:1230-1240.

Triazoles are among the most common systemic fungicides used in the control of plant diseases. Triazoles are absorbed and translocated in the plant, where they act preventively (before infection) or curatively (in the presence of symptoms) by affecting germ tube and appressoria formation or haustoria development and/or mycelial growth.2626 Buchenauer H. Mechanism of action of triazolyl fungicides and related compounds. In: Lyr H, ed. Modern Selective Fungicides: Properties, Applications, Mechanisms of Action. Harlow, United Kingdom: Longman Scientific and Technical; 1987:205–231.,2727 Pontzen R, Scheinpflug H. Effects of triazole fungicides on sterol biosynthesis during spore germination of Botrytis cinerea, Venturia inaequalis and Puccinia graminis f s: tritici. Netherlands. J Plant Pathol. 1989;95:151-160. By widening the window of protection beyond protectant fungicides, which act only preventatively and are not translocated, the advantages of triazoles represent a breakthrough in increasing the productivity of various crops affected by fungal diseases.22 Hof H. Critical annotations to the use of azole antifungals for plant protection. Antimicrob Agents Chemother. 2001;45:2987-2990. Around a third of all fungicides used for the protection of crop yields include triazoles, among which more than 99% are inhibitors of demethylation (DMI).2828 Chowdhary A, Kathuria S, Randhawa HS, Gaur SN, Klaassen CH. Isolation of multiple-triazole-resistant Aspergillus fumigatus strains carrying the TR/L98H mutations in the cyp51A gene in India. J Antimicrob Chemother. 2012;67:362-366. However, triazole fungicides are also known to present long-term stability, allowing them to remain active in certain ecological niches, such as soil and water, for several months.22 Hof H. Critical annotations to the use of azole antifungals for plant protection. Antimicrob Agents Chemother. 2001;45:2987-2990.,2929 Hamey PY, Harris CA. The variation of pesticide residues in fruits and vegetables and the associated assessment of risk. Regul Toxicol Pharmacol. 1999;30:34-41.

The number of antifungals available in the medical field for the treatment of systemic infections is relatively limited compared to those used for controlling diseases in plants, which is mainly due to problems related to erratic efficacy, drug toxicity, and intrinsic resistance.3030 Bergold AM, Georgiadis S. Novidades em fármacos antifúngicos: uma revisão new antifungic drugs: a review. Visão Acad. 2004;5:159-172. These compounds are usually effective in both topical and prophylactic treatments of invasive fungal infections.3131 Hay R. Antifungal drugs. In: Katsambas A, Lotti T, eds. European Handbook of Dermatological Treatments. Berlin, Germany: Springer; 2003:700–710. However, new triazoles that are less toxic to humans and with more specific targets have been investigated.3232 Carrillo-Munõz AJ, Giusiano G, Ezcurra PA, Quindóz G. Antifungal agents: mode of action yeast's cell. Rev Esp Quimioter. 2006;19:130-139.

33 Girmenia C. New generation azole antifungals in clinical investigation. Expert Opin Investig Drugs. 2009;18:1279-1295.
-3434 Pasqualotto AC, Thiele KO, Goldani LZ. Novel triazole antifungal drugs: focus on isavuconazole, ravuconazole and albaconazole. Curr Opin Investig Drugs. 2010;11:165-174. The first generation of triazoles for human therapy included itraconazole and fluconazole. The second generation is represented by voriconazole and posaconazole, which proved to be less toxic, safer, and with a broader spectrum of activity, including activity against fungi that were resistant to the previous generation.3535 Thompson GR, Cadena J, Patterson TF. Overview of antifungal agents. Clin Chest Med. 2009;30:203-215.,3636 Vandeputte V, Ferrari S, Coste AT. Antifungal resistance and new strategies to control fungal infections. Int J Microbiol. 2012;713687:1-26. Presently, isavuconazole, ravuconazole, and albaconazole are being investigated in phase III clinical trials as extended-spectrum triazoles with fungicidal activity against a wide number of clinically important fungi.

Development and monitoring of triazole resistance

The development of resistance to triazoles as a result of selective pressure by the continued use of regular or sub-regular dosages of fungicide is typically quantitative and expressed by a gradual change in the frequency of resistant isolates.1010 Deising HB, Reimann S, Pascholati SF. Mechanisms and significance of fungicide resistance. Braz J Microbiol. 2008;39:286-295. The main mechanisms involved have been reviewed and relate to the overexpression of the CYP51 gene due to mutations (insertions or duplications) in the promoter region and an increase in molecular efflux by ABC transporters caused by the overexpression of genes coding for membrane transport.99 Ma Z, Michailides TJ. Advances in understanding molecular mechanisms of fungicide resistance and molecular detection of resistant genotypes in phytopathogenic fungi. Crop Prot. 2005;24:853-863.,3737 Coleman JJ, Mylonakis E. Efflux in fungi: la pièce de résistance. PLoS ONE. 2009;5:1-7.,3838 Ammar GA, Tryono R, Do K, Karlovsky P, Deising HB, Wirsel SGR. Identification of ABC transporter genes of Fusarium graminearum with roles in azole tolerance and/or virulence. PLoS ONE. 2013;8:2-13. Recently, a study that examined A. fumigatus isolates from a range of clinical environments suggested point mutations of CYP51 and TR34/L98H genomic regions in isolates obtained from patients with long term use of triazole-based therapy for the treatment of chronic aspergillosis.1616 Lelièvre L, Groh M, Angebault C, Maherault AC, Didier E, Bougnoux ME. Azole resistant Aspergillus fumigatus: an emerging problem. Med Mal Infect. 2013;43:139-145.

A key element in the sustainable use of fungicides is to monitor the sensitivity of the pathogen population to a certain compound.3939 Parnell S, van den Bosch F, Gilligan CA. Large-scale fungicide spray heterogeneity and the regional spread of resistant pathogen strains. Phytopathology. 2006;96:549-555.

40 Suzuki F, Yamaguchi J, Koba A, Nakajima T, Arai M. Changes in fungicide resistance frequency and population structure of Pyricularia oryzae after discontinuance of MBI-D fungicides. Plant Dis. 2010;94:329-334.
-4141 Van der Heyden H, Dutilleul P, Brodeur L, Carisse O. Spatial distribution of single nucleotide polymorphisms related to fungicide resistance and implications for sampling. Phytopathology. 2014;104:604-613. There are a number of direct and indirect methods recommended for specific fungi that are aimed at estimating the EC50 (effective concentration at which 50% of fungal growth is inhibited) and MIC (minimum inhibitory concentration) values.1010 Deising HB, Reimann S, Pascholati SF. Mechanisms and significance of fungicide resistance. Braz J Microbiol. 2008;39:286-295.,4242 Edgington LV, Khnw KL, Barron GL. Fungitoxic spectrum of benzimidazole compounds. Phytopathology. 1971;61:42-44.

43 Liu X, Yin Y, Wu J, Jiang J, Ma Z. Identification and characterization of carbendazim-resistant isolates of Gibberella zeae. Plant Dis. 2010;94:1137-1142.

44 Spolti P, Jorge BC, Del Ponte EM. Sensitivity of Fusarium graminearum causing head blight of wheat in Brazil to tebuconazole and metconazole fungicides. Trop Plant Pathol. 2012;37:419-423.
-4545 Spolti P, Del Ponte EM, Dong Y, Cummings JA, Bergstrom GC. Triazole sensitivity in a contemporary population of Fusarium graminearum from New York wheat and competitiveness of a tebuconazole-resistant isolate. Plant Dis. 2014;98:607-613.

In the medical field, the surveillance and prevention of resistance to antifungal agents have been subject to many restrictive actions in recent years. More specifically, the FDA (Food and Drug Administration) and the EMA (European Medicines Agency) regulate and approve the use of antimicrobials in North America and Europe, respectively.4646 Aparicio JF, Mendes MV, Antón N, Recio E, Martín JF. Polyenemacrolide antiobiotic biosynthesis. Curr Med Chem. 2004;1:645-1656. Simultaneously, the Clinical and Laboratory Standards Institute (CLSI), together with the Subcommittee on Antifungal Susceptibility Testing (AFST) of the European Committee for Antimicrobial Susceptibility Testing (EUCAST), publish in vitro test protocols periodically for monitoring fungi sensibility to antifungal agents of clinical and veterinary use. These actions allow for the standardization of parameters for the evaluation of in vitro resistance in the laboratory. However, these actions and protocols do not involve the monitoring of resistance of plant pathogenic fungi, thus challenging the use of antifungal agents in clinical therapy.

In agriculture, the Fungicide Resistance Action Committee (FRAC), a technical group maintained by the industry, provides guidelines for the management of fungicide resistance, such as the need to estimate a baseline resistance level in isolates sampled from the population prior to the commercial use of a fungicide.4747 Brent KJ, Hollomon DW. Fungicide resistance in crop pathogens: how can it be managed? FRAC Monograph n.1.2007. During commercial use, reports of failures in disease control and detection of resistant isolates (those with sensitivity levels lower than the baseline) are indicators of the risk of developing fungicide resistance.4747 Brent KJ, Hollomon DW. Fungicide resistance in crop pathogens: how can it be managed? FRAC Monograph n.1.2007. Periodically, information is provided by the FRAC about the risk of plant pathogens that ranges from low to high. Currently, many studies are known that report steadily increasing resistance to triazoles in plant pathogenic fungi.4848 FRAC. FRAC cod list. FRAC information: list of resistance. Available in: http://www.frac.brasil.org.br (accessed 05.05.15).
http://www.frac.brasil.org.br...

Triazole resistance in clinical isolates and agricultural use

In the medical field, the first report of DMI's resistance in A. fumigatus isolates dates back more than three decades ago. However, the resistance to itraconazole by Aspergillus spp. from the clinical environment was first reported in 1997 for three isolates obtained from California in the late 1980s.4949 Denning DW, Venkateswarlu K, Oakley KL, Anderson MJ, Manning PJ, Stevens DA. Itraconazole resistance in Aspergillus fumigatus. Antimicrob Agents. 1997;41:1364-1368. The prescription of triazoles as a preferential choice for the treatment of patients with respiratory diseases has been considered to contribute to the development of resistance to this group of fungicides.1010 Deising HB, Reimann S, Pascholati SF. Mechanisms and significance of fungicide resistance. Braz J Microbiol. 2008;39:286-295.,5050 Shao PL, Huang LM, Hsueh PR. Recent advances and challenges in the treatment of invasive fungal infections. Int J Antimicrob Agents. 2007;6:487-495.,5151 Gore RB. The utility of antifungal agents asthma. Curr Opin Pulm Med. 2010;16:36-41. Multidrug-resistance (MDR)5252 Gulshan K, Moye-Rowley WS. Multidrug resistance in fungi. Eukaryot Cell. 2007;6:1933-1942. is considered to be the cause of the failure of a wide range of antifungal agents available on the market.5353 Fischbach MA, Walsh CT. Antibiotics for emerging pathogens. Science. 2009;325:1089-1093.,5454 Pfaller MA, Diekema DJ. Progress in antifungal susceptibility testing of Candida sp.: by use of clinical and laboratory standards institute broth microdilution methods, 2010 to 2012. J Clin Microbiol. 2012;50:2846-2856. As an emergent fungus in clinical environments, A. fumigatus holds a history of cross-resistance and multi-resistance to azoles.5555 Howard SJ, Webster I, Moore CB, Gardiner RE, Park S, Perlin DS. Multi-azole resistance in Aspergillus fumigatus. Int J Antimicrob Agents. 2006;28:450-453. It is probable that millions of people are not effectively treated due to infections by fungi exhibiting antifungal resistance, among which 4.8 million cases are related only to the species of Aspergillus.5656 Denning D, Pleuvry A, Cole D. Global burden of ABPA in adults with asthma and its complication chronic pulmonary aspergillosis in adults. Med Mycol. 2013;51:361-370. The triazole antifungals commonly used in the medical field for the treatment of fungal diseases and pathogens that have exhibited some level of resistance are listed in Table 1.

Table 1
Pathogenic fungi with intrinsic or developed resistance to triazoles for human therapeutic use.

It has been shown that exposure of environmental fungi to triazole fungicides may cause shifts from susceptible to resistant populations, especially in the absence of adaptive costs which may facilitate the spread of resistant populations into diverse environments.5757 Verweij E, Kema GH, Zwaan B, Melchers WJ. Triazole fungicides and the selection of resistance to medical triazoles in the opportunistic mould Aspergillus fumigatus. Pest Manage Sci. 2013;69:165-170. The surge of "emerging fungi" in the medical field or fungi that are otherwise harmless to humans, such as the zygomycetes and other hyaline filamentous fungi,22 Hof H. Critical annotations to the use of azole antifungals for plant protection. Antimicrob Agents Chemother. 2001;45:2987-2990.,5757 Verweij E, Kema GH, Zwaan B, Melchers WJ. Triazole fungicides and the selection of resistance to medical triazoles in the opportunistic mould Aspergillus fumigatus. Pest Manage Sci. 2013;69:165-170. has led some authors to hypothesize that other mechanisms may be leading to resistance, such as the large amount of fungicides used in agroecosystems.77 Brown GD, Denning DW, Levitz SM. Tackling human fungal infections. Science. 2012;336:647.,5858 Ruping MJGT, Vehreschil JJ, Cornely OA. Patients at high risk of invasive fungal infections: when and how to treat. Drugs. 2008;68:1941-1962.,5959 Tobudic S, Kratzer C, Presterl E. Azole-resistant Candida sp.: emerging pathogens. Mycoses. 2012;55:24-32. This hypothesis was initially suggested by studies conducted in the Netherlands1313 Snelders E, van der Lee HA, Kuijpers J, Rijs AJMM, Varga J. Emergence of azole resistance in Aspergillus fumigatus and spread of a single resistance mechanism. PLOS Med. 2008;5:1629-1637. and later corroborated by studies conducted in Spain,6060 Rodriguez-Tudela JL, Alcazar-Fuoli L, Mellado E, Alastruey-Izquierdo A, Monzon A, Cuenca-Estrella M. Epidemiological cutoffs and cross-resistance to azole drugs in Aspergillus fumigates. Antimicrob Agents Chemother. 2008;52:2468-2472. Belgium,1313 Snelders E, van der Lee HA, Kuijpers J, Rijs AJMM, Varga J. Emergence of azole resistance in Aspergillus fumigatus and spread of a single resistance mechanism. PLOS Med. 2008;5:1629-1637. Norway,1313 Snelders E, van der Lee HA, Kuijpers J, Rijs AJMM, Varga J. Emergence of azole resistance in Aspergillus fumigatus and spread of a single resistance mechanism. PLOS Med. 2008;5:1629-1637. Great Britain,6161 Howard SJ, Pasqualotto AC, Denning DW. Azole resistance in allergic bronchopulmonary aspergillosis and Aspergillus bronchitis. Clin Microbiol Infect. 2010;16:683-688. Denmark,6262 Mortensen KL, Mellado E, Lass-Flörl C, Rodriguez-Tudela JL, Johansen HK. Environmental study of azole-resistant Aspergillus fumigatus and other aspergilli in Austria, Denmark, and Spain. Antimicrob Agents Chemother. 2010;54:4545-4549. France,6363 Burgel PR, Baixench MT, Amsellem M, Audureau E, Chapron J, Kanaan R. High prevalence of azole-resistant Aspergillus fumigatus in adults with cystic fibrosis exposed to itraconazole. Antimicrob Agents Chemother. 2012;56:869-874. China,6464 Lockhart SR, Frade JP, Etienne KA, Pfaller MA, Diekema DJ, Balajee SA. Azole resistance in Aspergillus fumigatus isolates from the ARTEMIS global surveillance study is primarily due to the TR/L98H mutation in the cyp51A gene. Antimicrob Agents Chemother. 2011;55:4465-4468. Italy,6565 Van der Linden JW, Arendrup MC, Verweij PE. SCARE-Network. Prospective International Surveillance of AzoleResistance in Aspergillus fumigatus (SCARE-Network). Chicago, USA: ICAAC; 2011. Austria,6565 Van der Linden JW, Arendrup MC, Verweij PE. SCARE-Network. Prospective International Surveillance of AzoleResistance in Aspergillus fumigatus (SCARE-Network). Chicago, USA: ICAAC; 2011. and India.2828 Chowdhary A, Kathuria S, Randhawa HS, Gaur SN, Klaassen CH. Isolation of multiple-triazole-resistant Aspergillus fumigatus strains carrying the TR/L98H mutations in the cyp51A gene in India. J Antimicrob Chemother. 2012;67:362-366.

A few studies have jointly examined the sensitivity of isolates that cause diseases in both plants and humans to triazoles. These studies suggested that the selection of fungicides with a similar mode of action as those used in human drug therapy for triazole-resistant isolates could contribute to the development of multi-resistant populations.6666 Meneau I, Sanglard D. Azole and fungicide resistance in clinical and environmental Aspergillus fumigatus isolates. Med Mycol. 2005;43:307-311.,6767 Drummond DE, Reimão JQ, Dias ALT, Siqueira AM. Comportamento de mostras ambientais e clínicas de Cryptococcus neoformans frente a fungicidas de uso agronômico e ao fluconazol. Rev Soc Bras Med Trop. 2007;2:209-211. The development of cross-resistance to triazoles and the low number of triazoles recommended for human therapy relative to the high number of triazoles used in agriculture may affect triazole efficacy for human therapy.66 Snelders E, Huis In't Veld RA, Rijs AJ, Kema GH, Melchers WJ, Verweij PE. Possible environmental origin of resistance of Aspergillus fumigatus to medical triazoles. Appl Environ Microbiol. 2009;75:4053-4057.,1010 Deising HB, Reimann S, Pascholati SF. Mechanisms and significance of fungicide resistance. Braz J Microbiol. 2008;39:286-295. For instance, the fungus Colletotrichum graminicola that causes anthracnose of corn plants is an emerging pathogen in humans. Resistance to tebuconazole as well as to multiple other azole antifungals has been reported in plant pathogenic populations used in clinical medicine.6868 O'Quinn RP, Hoffman JL, Boyd AS. Colletotrichum species as emerging opportunistic fungal pathogens: a report of 3 cases of phaeohyphomycosis and review. J Am Acad Dermatol. 2001;l45:56-61.,6969 Serfling A, Wohlrab J, Deising HB. Treatment of a clinically relevant plant pathogenic fungus with an agricultural azole causes cross-resistance to medical azoles and potentiates caspofungin efficacy. Antimicrob Agents Chemother. 2007;51:3672-3676. Similarly, cross-resistance to triazoles was observed in clinical isolates of Candida albicans and agricultural environmental yeasts.7070 Müller FM, Staudigel A, Salvenmoser S, Tredup A, Miltenberger R, Herrmann JV. Cross-resistance to medical and agricultural azole drugs in yeasts from the oropharynx of human immunodeficiency virus patients and from environmental Bavarian vine grapes. Antimicrob Agents Chemother. 2007;51:3014-3016.

Several other fungi have been found in association with human and animal diseases, including species of several genera such as Bipolaris, Macrophomina, Aspergillus, Fusarium, Alternaria and Mucor1818 De Lucca AJ. Harmful fungi in both Agriculture and Medicine. Rev Iberoam Micol. 2007;24:3-13.,7171 Mehanna HM, Kuo T, Chaplin J, Taylor G, Morton RP. Fungal laryngitis in immunocompetent patients. J Laryngol Otol. 2004;118:379-381.

72 Srinivasan A, Wickes BL, Romanelli AM, Debelenko L, Rubnitz JE. Cutaneous Infection caused by Macrophomina phaseolina in a child with acute myeloid leukemia. J Clin Microbiol. 2009;47:1969-1972.
-7373 Cunha KC, Sutton DA, Fothergill AW, et al. Diversity of Bipolaris species in clinical samples in the United States and their antifungal susceptibility profiles. J Clin Microbiol. 2012;50:4061-4066. (Table 2). The pathogenicity of clinical isolates of the Fusarium solani species complex was confirmed in plants of the Cucurbitacea family, which exhibited similar aggressiveness to isolates originating from diseased plants.1717 Mehl HL, Epstein L. Fusarium solani species complex isolates conspecific with F. solani f. s: cucurbitae race 2 from naturally infected human and plant tissue and environmental sources are equally virulent on plants, grow at 37 °C and are interfertile. Environ Microbiol. 2007;9:2189-2199.Criptococcus neoformans is also found in different environmental niches, such as plants and animals.7474 Chowdhary A, Randhawa HS, Sundar G, et al. In vitro antifungal susceptibility profiles and genotypes of 308 clinical and environmental isolates of Cryptococcus neoformans var. grubii and Cryptococcus gattii serotype B from north-western India. J Med Microbiol. 2011;60:961-967. Fluconazole is the most prevalent clinical antifungal used to treat cryptococcosis.7575 Gullo FP, Rossi SA, Sardi Jde C, Teodoro VL, Mendes-Giannini MJ, Fusco-Almeida AM. Cryptococcosis: epidemiology, fungal resistance, and new alternatives for treatment. Eur J Clin Microbiol Infect Dis. 2013;32:1377-1391. However, the continued use of this antifungal is an increasing concern due to the frequency of isolates resistant to triazoles used in human therapeutic use.7676 Paul S, Doering TL, Moye-Rowley WS. Cryptococcus neoformans Yap1 is required for normal fluconazole and oxidative stress resistance. Fungal Genet Biol. 2015;74:1-9. There is a need for attention to azole resistance and optimal therapy in regions with high incidence of cryptococcosis, such as the Asian-Pacific region (5.1-22.6%), Africa/Middle-East (7.0-33.3%), and Europe (4.2-7.1%).7777 Pfaller MA, Diekema DJ, Gibbs DL, et al. Results from the ARTEMIS DISK Global Antifungal Surveillance Study, 1997 to 2007: 10-year analysis of susceptibilities of noncandidal yeast species to fluconazole and voriconazole determined by CLSI standardized disk diffusion testing. J Clin Microbiol. 2009;47:117-123. In addition to fluconazole resistance in these regions, the new point of mutation in the ERG11 gene of C. neoformans afforded resistance to voriconazole (VRC).7878 Sionov E, Lee H, Chang YC, Kwon-Chung KJ. Cryptococcus neoformans overcomes stress of azole drugs by formation of disomy in specific multiple chromosomes. PLoS Pathog. 2010;6:1-13. In these cases, the spread of isolates exhibiting resistance to triazoles into the environment and those capable of causing human diseases may affect the efficacy of therapeutic control with fungicides of the same group, especially in the presence of cross-resistance.7979 Williams DA, Lemke TL. Foye's Principles of Medicinal Chemistry. 5ªed. New Jersey, USA: Philadelphia, Lippincot Williams and Wilkins; 2002.

Table 2
Main genera of fungi reported as the causative agents of diseases in plants and in humans.

The mutagenesis in TR34/L98H in azole-resistant Aspergillus may have originated due to the use of triazole fungicides in agroecosystems.1414 Snelders E, Camps SM, Karawajczyk A, et al. Triazole fungicides can induce cross-resistance to medical triazoles in Aspergillus fumigatus. PLoS ONE. 2012;7:e31801.,2828 Chowdhary A, Kathuria S, Randhawa HS, Gaur SN, Klaassen CH. Isolation of multiple-triazole-resistant Aspergillus fumigatus strains carrying the TR/L98H mutations in the cyp51A gene in India. J Antimicrob Chemother. 2012;67:362-366.,8080 Singh PK, Gaur SN, Hagen F, et al. Possible environmental origin of resistance of Aspergillus fumigatus to medical triazoles. Appl Environ Microbiol. 2009;75:4053-4057. Such mutation was detected in 89% of A. fumigatus-resistant isolates from air samples, flowers, and soils from hospital areas.66 Snelders E, Huis In't Veld RA, Rijs AJ, Kema GH, Melchers WJ, Verweij PE. Possible environmental origin of resistance of Aspergillus fumigatus to medical triazoles. Appl Environ Microbiol. 2009;75:4053-4057. Microsatellite sequencing of clinical and environmental isolates that lead to the TR34/L98H mutation revealed high genetic homology, which suggests a common ancestor.66 Snelders E, Huis In't Veld RA, Rijs AJ, Kema GH, Melchers WJ, Verweij PE. Possible environmental origin of resistance of Aspergillus fumigatus to medical triazoles. Appl Environ Microbiol. 2009;75:4053-4057.,1313 Snelders E, van der Lee HA, Kuijpers J, Rijs AJMM, Varga J. Emergence of azole resistance in Aspergillus fumigatus and spread of a single resistance mechanism. PLOS Med. 2008;5:1629-1637.

Future directions

Triazole antifungals largely used in plant protection are also important as antifungal treatments in the human medical field even though they possessing structural differences. However, sensitive populations that co-inhabit environments may be reduced by the selection of isolates resistant to fungicides. Fungi arising from agricultural ecosystems as opportunistic pathogens may carry cross-resistance to triazoles used in the medical field. The restricted number of antifungal agents for clinical use, which contrasts with the large number of agricultural fungicides with similar modes of action, may be a risk factor that limits the success of the therapeutic use of these drugs.

Currently, genome-wide studies, together with novel T-cell-based therapeutic approaches for the prophylaxis and treatment of opportunistic fungal infections, have promising avenues of research in the detection of potentially new antifungal targets.8181 Barrera A, Alastruey-Izquierdo A, Martín MJ, Cuesta I, Vizcaíno JA. Analysis of the protein domain and domain architecture content in fungi and its application in the search of new antifungal targets. PLoS Comput Biol. 2014;10:1-16.,8282 Mancini N, Marrone L, Clementi N, Sautto GA, Clementi M, Burioni R. Adoptive T-cell therapy in the treatment of viral and opportunistic fungal infections. Future Microbiol. 2015;10:665-682. Thus, different strategies should be the main goals of the pharmaceutical industry.

Given that the search for new antifungal drugs is a lengthy process, the combination of drugs to achieve synergistic effects is currently adopted as an alternative. This approach includes the combination of drugs with distinct mechanisms of action that may enhance efficacy by combining low concentrations of both antifungal agents, thus diminishing the risk of developing resistance.

Acknowledgments

The authors are thankful to the Coordenação de Aperfeiçoamento de Pessoal de nível superior - CAPES for financial support. A.M. Fuentefria and H.S. Schrekker are grateful to CNPq for the PQ fellowships.

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Publication Dates

  • Publication in this collection
    Oct-Dec 2016

History

  • Received
    26 Nov 2014
  • Accepted
    4 Mar 2016
Sociedade Brasileira de Microbiologia USP - ICB III - Dep. de Microbiologia, Sociedade Brasileira de Microbiologia, Av. Prof. Lineu Prestes, 2415, Cidade Universitária, 05508-900 São Paulo, SP - Brasil, Ramal USP 7979, Tel. / Fax: (55 11) 3813-9647 ou 3037-7095 - São Paulo - SP - Brazil
E-mail: bjm@sbmicrobiologia.org.br