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Mechanisms of resistance against allylamine and azole antifungals in Trichophyton: A renewed call for innovative molecular diagnostics in susceptibility testing

Abstract

The emergence of antifungal resistance calls for continued research efforts to better guide healthcare providers in treatment selection and outcomes. Unlike bacterial infections, treatment of superficial fungal infections is mainly limited to allylamines (terbinafine) and azoles (itraconazole). Here, we aim to update our current understanding of resistance mechanisms against allylamine and azole antifungals in the Trichophyton genus. Resistance development has been demonstrated in vitro by challenging Trichophyton isolates with allylamines or azoles at levels below the minimum inhibitory concentration (MIC), which corroborates the observation of clinical resistance. Frequently reported mechanisms of resistance include: (I) Alterations of the drug target by single-nucleotide variations (SNVs) of the SQLE/ERG1 and ERG11 genes; in particular, SQLE SNVs (Leu393Phe, Leu393Ser, and Phe397Leu) have been frequently reported in isolates with high terbinafine MICs; (II) overexpression of the target enzyme for azoles (ERG11) and downstream genes in the ergosterol biosynthesis pathway can decrease the effective drug concentration as well as prevent the depletion of ergosterol and the accumulation of toxic sterol intermediates; (III) the up-regulation of drug efflux channels—belonging to the ABC superfamily (PDR1, MDR2, MDR3, MDR4), MFS superfamily (MFS1), or Pma1 (plasma membrane ATPase 1)—can reduce the effective concentrations of terbinafine and azoles. The possibility of multidrug resistance has been shown in Trichophyton strains, of both human and animal origins, harboring multiple resistance mechanisms (e.g., target alteration/overexpression and drug efflux channels). Tackling the issue of antifungal resistance will require an integrated approach with multidisciplinary efforts including surveillance initiatives and antifungal stewardship programs. However, these efforts are hampered by the current limited accessibility of antifungal susceptibility testing as well as the limited choice of antifungals available in routine practice. A better understanding of resistance mechanisms could help develop targeted, molecular-based assays.

Author summary

Fungal infections of the skin, hair, and nails affect up to one quarter of the world’s population. Unlike treatments for bacterial infections, the number of options for the treatment of superficial fungal infections is more limited, which typically belongs to 2 types of drugs—allylamines (terbinafine) and azoles (itraconazole). In recent years, resistant superficial fungal infections have been increasingly reported globally. However, resistance testing and surveillance have proven to be difficult due to technical limitations. In this article, we aim to update our current understanding of several resistance mechanisms found in superficial fungal infections caused by the Trichophyton genus. A better understanding of these mechanisms can aid in the development of advanced molecular diagnostics in place of traditional methods. Common resistance mechanisms identified to date include alterations and overexpressions of the drug target, as well as efflux pumps that reduces the effective drug concentration inside the cell. Resistance can develop due to insufficient drug dosages; once developed, these resistant strains may spread through travel and person-to-person contact. Furthermore, certain wild and domestic animals may carry resistant strains.

Citation: Gupta AK, Wang T, Mann A, Piguet V, Chowdhary A, Bakotic WL (2025) Mechanisms of resistance against allylamine and azole antifungals in Trichophyton: A renewed call for innovative molecular diagnostics in susceptibility testing. PLoS Pathog 21(2): e1012913. https://doi.org/10.1371/journal.ppat.1012913

Editor: Mary Ann Jabra-Rizk, University of Maryland, Baltimore, UNITED STATES OF AMERICA

Published: February 11, 2025

Copyright: © 2025 Gupta et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: The authors received no specific funding for this work.

Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Authors AKG, TW, AM and AC have declared that no competing interests exist. Author VP has no personal financial ties with any pharmaceutical company. He has received honoraria for speaker and/or advisory board member roles from AbbVie, Celgene, Janssen, Kyowa Kirin Co. Ltd, LEO Pharma, Novartis, Pfizer, Sanofi, UCB, and Union Therapeutics. In his role as Department Division Director of Dermatology at the University of Toronto, VP has received departmental support in the form of unrestricted educational grants from AbbVie, Bausch Health, Celgene, Janssen, LEO Pharma, Lilly, L’Oréal, NAOS, Novartis, Pfizer, Sandoz and Sanofi in the past 36 months. Author WLB is an employee of Bako Diagnostics (Alpharetta, GA, USA).

Introduction

Treatment failure is not uncommon when it comes to the management of dermatophytosis. Beginning with the introduction of griseofulvin in 1959 (Fig 1), the field of antifungal resistance research has seen an upsurge in recent years due to the waning effectiveness of terbinafine, the most commonly prescribed and cheapest antifungal globally [1,2]. The rising number of cases resistant to terbinafine have been reported globally, and the worldwide spread has been attributed to an outbreak of recalcitrant dermatophytoses in the Indian subcontinent due to Trichophyton indotineae [2].

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Fig 1. Timeline of oral antifungal developments and resistance reporting for the management of dermatophytosis [3–9].

https://doi.org/10.1371/journal.ppat.1012913.g001

To optimize treatment selection, antifungal susceptibility testing (AFST) has been introduced, and standardized protocols were established by the Clinical and Laboratory Standards Institutes (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) [10]. Through the determination of the minimum inhibitory concentration (MIC)—in reference to the clinical breakpoint—isolates can be categorized as wild-type or resistant to a particular drug. Based on AFST results, treatment selection can be guided using the 90/60 rule which predicts that approximately 90% of infections by wild-type isolates will respond to therapy while approximately 60% of infections by resistant isolates will respond to therapy [11].

Performing AFST for dermatophytes faces numerous challenges [10], namely, the lack of clinical breakpoints to define resistant strains, reliance on fungal culture with a low recovery rate, high costs and need for specialized laboratory resources. In an attempt to increase the uptake and expand the accessibility of AFST, newer methodologies targeting specific resistance markers, without requiring the growth of isolates in culture, have been introduced [10]. In this review, we aim to summarize currently available literature on the landscape of resistance mechanisms against allylamine and azole antifungals in the Trichophyton genus.

Trichophyton indotineae resistant to terbinafine and azoles

The issue of antifungal resistance—particularly against terbinafine—has been brought into focus by the outbreak of a newly discovered Trichophyton species, T. indotineae (formerly T. mentagrophytes genotype VIII). T. indotineae infection represents a distinct clinical entity that can present as widespread, pruritic tinea corporis or tinea cruris [2]. Atypical features (e.g., eczema-like, psoriasis-like) can also be observed. Although extensive dermatophytoses were once considered a risk mainly for immunocompromised individuals, this no longer appears to be the case with T. indotineae infections [12].

A multitude of studies across continents have reported resistance mechanisms in T. indotineae isolates, which is mostly correlated with in vitro terbinafine resistance and less frequently against azoles [12–17]. However, current available data do not support the notion that T. indotineae is intrinsically resistant against terbinafine, and the alternative use of azoles (e.g., itraconazole, voriconazole) is complicated by its varied bioavailability and safety concerns [2]. Therefore, it is becoming ever more apparent that AFST should be made easily accessible across different healthcare settings to ensure appropriate treatment selection and reduce patient suffering.

Mechanisms of resistance in Trichophyton rubrum and Trichophyton mentagrophytes complex

Studies have demonstrated the potential for resistance development when Trichophyton isolates are repeatedly challenged with low concentrations of antifungals in vitro; for example, a 2-fold increase in MICs was reported after exposing clinical T. rubrum isolates to fluconazole and itraconazole [18]. After a period of exposure to increasing concentrations of terbinafine, a wild-type T. rubrum strain acquired the Phe397Leu substitution in the squalene epoxidase gene (SQLE/ERG1) corroborated by an increase in terbinafine MIC from <0.03 to >32 μg/ml [19]. An overview of resistance mechanisms is shown in Fig 2.

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Fig 2. Summary of resistance mechanisms against allylamines and azoles in Trichophyton.

(A) Single-nucleotide variations of SQLE or ERG11; (B) up-regulation of drug efflux channels; (C) overexpression of the target enzyme (ERG11) for azole antifungals and downstream genes in the ergosterol biosynthesis pathway; (D) up-regulation of the heat shock response (Hsp90); (E) overexpression of salA as part of the naphthalene degradation pathway; (F) biofilm formation. Three visual elements shown in this figure were modified/reused in accordance with the CC BY 4.0 license (Martinez-Rossi and colleagues [20]), with attribution (2D structure image of terbinafine: PubChem Identifier: 1549008; https://pubchem.ncbi.nlm.nih.gov/compound/1549008#section=Structures), or are in the public domain (https://commons.wikimedia.org/wiki/File:Hsp90.png).

https://doi.org/10.1371/journal.ppat.1012913.g002

Increased expression and posttranscriptional regulation of drug efflux channels, belonging to either the ABC (ATP-binding cassette) or MFS (major facilitator superfamily) superfamilies, have been reported in response to terbinafine and azoles [21–30]. Overexpression of Erg enzymes (ergosterol biosynthesis pathway) has been implicated to induce resistance—in particular against azoles—by diluting the effective drug concentration [26,28,31–33]. In strains harboring multiple resistance mechanisms (e.g., SQLE mutation and up-regulation of drug efflux channels), the possibility for developing multidrug resistance has been raised [31,34,35]. Other plausible resistance mechanisms with sparse reports that warrants further clinical validation include biofilms [36], the heat shock response [37], and up-regulation of the naphthalene degradation pathway [38].

Single-nucleotide variations in the genes encoding squalene epoxidase (SQLE/ERG1) and lanosterol 14-α-demethylase (ERG11) in Trichophyton spp.

Through the induction of enzyme conformational changes that inhibit drug-binding, single-nucleotide variations (SNVs) in the SQLE gene have been frequently reported as a mechanism for terbinafine resistance. Phe397Leu is the most common in T. rubrum, the T. mentagrophytes complex and T. indotineae (Fig A and Appendx A and References in S1 Text). The Ala448Thr substitution thus far has only been reported in the T. mentagrophytes complex and T. indotineae; in contrast, substitution at the 440His position is more commonly observed in T. rubrum.

Based on computational modeling, both 393Leu and 397Phe have been shown to be located adjacent to the terbinafine binding pocket on the squalene epoxidase enzyme [12,13,39,40], this prediction is corroborated by the observation of high terbinafine MICs in strains carrying the Leu393Phe, Leu393Ser, or Phe397Leu substitutions—where almost all strains could be classified as non wild type—confirmed by both CLSI and EUCAST protocols (Table A in S1 Text). Furthermore, Leu393Ser has been predicated to significantly alter the SQLE binding affinity to terbinafine [13]. The 448Ala amino acid position, however, is not adjacent to the terbinafine binding pocket and its functional significance warrants further investigation [12,13]. Of interest, a decreased susceptibility to azoles may be associated with the Ala448Thr substitution [12,15,16]. AFST results by both CLSI and EUCAST protocols suggest that strains with the Ala448Thr substitution exhibit high susceptibility to terbinafine (Table A in S1 Text).

SNVs in the ERG11 gene conferring decreased susceptibility to azoles are not as frequently reported. ERG11 in dermatophytes has 2 isoforms, ERG11A and ERG11B. Winter and colleagues reported an ERG11A substitution unique to T. quinckeanum strains with in vitro resistance against fluconazole and itraconazole [41]. No ERG11A SNVs have been reported in other Trichophyton spp. thus far. However, several ERG11B substitutions have been reported in T. indotineae without a correlation to azole resistance [42,43].

Overexpression of ergosterol biosynthesis pathway enzymes in Trichophyton spp.

As a counter to the depletion of ergosterol and the accumulation of toxic sterol intermediates by allylamines and azoles, the overexpression of target enzymes may serve as a detoxification mechanism. After acquiring itraconazole-resistance in vitro, a T. mentagrophytes complex strain exhibited an up-regulation of ERG11 as well as higher quantities of ergosterol compared to a sensitive strain [31]; another study identified the up-regulation of a downstream gene, ERG25, in response to clotrimazole [32]. In fluconazole-resistant T. verrucosum strains of human and animal origins, an increased expression of ERG11 as well as 2 downstream genes in the ergosterol biosynthesis pathway (ERG6, ERG3) was found [44].

Recently, an overexpression of ERG11B as tandem repeats was discovered by Yamada and colleagues in T. indotineae strains resistant to itraconazole and voriconazole, while ERG11A was overexpressed to a lesser extent [15,16]. An elevated expression of MDR3 and the presence of SQLE SNVs were also found suggesting the possibility of multidrug resistance [15].

Drug efflux channels in Trichophyton spp.

Drug efflux channels—commonly identified as belonging to the ABC or MFS superfamilies in the fungal genome—are integral membrane proteins that mediate the movement of molecules [45]. The ABC-B subfamily (PDR1, MDR2, MDR3, and MDR4) has been associated with multidrug resistance and are abundantly expressed in Trichophyton [46]. Exposing clinical Trichophyton strains to terbinafine and itraconazole led to a heightened expression of the ABC-B transporters [22].

In a T. rubrum strain with decreased susceptibility to itraconazole, voriconazole and terbinafine isolated from a tinea corporis patient, Kano and colleagues reported an increased expression of MDR3 and MDR4 in tandem with the detection of Leu393Phe in the SQLE gene [47]. In another multiresistant T. rubrum strain, the Phe397Leu substitution in the SQLE gene was detected as well as an increase in expression of MDR2 and MDR3 [48]; a follow-up study identified MDR2 as a major contributor to itraconazole resistance [27]. For resistant strains of the T. mentagrophytes complex, an overall increase in MDR expression concurrent with the detection of Phe397Leu in the SQLE gene was reported [28]; challenging these strains with itraconazole in vitro led to an increased expression of PDR1, MDR2, and MDR3, while terbinafine increased the expression of PDR1 [28].

Of the MFS superfamily conferring antifungal resistance, MFS1 has been implicated in fluconazole and miconazole resistance in the T. mentagrophytes complex [30]. Another potential drug efflux channel (Pma1; plasma membrane ATPase 1) was recently reported by Ishii and colleagues to play a role in terbinafine resistance using T. rubrum and may be complementary to the effects of SQLE SNVs (Leu393Phe, Phe397Leu) [49].

Besides an elevated level of expression, point mutations and posttranscriptional regulation of transporter genes may increase the functional diversity of the efflux channels, further contributing to resistance development. PDR1 and MFS SNVs were found in a T. mentagrophytes complex strain from a patient unresponsive to terbinafine and itraconazole [34]. An alternative splicing event of an efflux pump gene, generating an intron-retained isoform, was reported in association with the itraconazole response in T. rubrum [50].

Biofilms in Trichophyton spp.

The extent of biofilm involvement in the pathogenesis of dermatophytosis is unclear. Biofilms are organized assemblages of microbial communities—sessile and adherent—protected by an extracellular matrix enriched in polysaccharides. When assessing the antifungal susceptibility profile of Trichophyton biofilms against planktonic cells or non-biofilm producers in vitro, Trichophyton biofilms were less susceptible to terbinafine, itraconazole, econazole, and voriconazole [51–53]. In one study, inhibiting the growth of Trichophyton biofilms required itraconazole and voriconazole concentrations at 50 times the MIC than that of planktonic cells [52]. An increase in biofilm thickness—linked to an up-regulation of ERG25 and CYP450 genes—was reported by Xiao and colleagues as a response against clotrimazole in the T. mentagrophytes complex, further highlighting the roles of biofilms in antifungal resistance [32]. In the context of mixed infection, a polymicrobial biofilm composed of T. rubrum with Candida albicans or C. parapsilosis may be resistant to terbinafine and efinaconazole [54].

In onychomycosis, the secondary development of dermatophytoma (i.e., compacted fungal elements forming a “fungal ball”) complicating treatment is believed to be associated with the formation of biofilms [55]. In 2 patients infected with terbinafine-resistant T. rubrum (SQLE SNV: Leu393Phe) and T. mentagrophytes var. interdigitale (SQLE SNV: Phe397Leu), the presence of dermatophytoma was evidenced by the concentrated quantities of hyphae and arthroconidia as well as extracellular polysaccharides [36,56]. Besides reducing drug penetration, studies of C. albicans biofilms show an up-regulation of drug efflux channels as well as the transition into a state of metabolic quiescence (i.e., dormant cells) that further contributes to antifungal resistance [57,58].

Conclusions

In recent years, the issue of terbinafine resistance in Trichophyton has evolved from sporadic incidents into a matter of public health concern [59,60]. The cause for resistance development may be subtherapeutic dosing, evidenced by the observation of in vitro resistance development when Trichophyton spp. are repeatedly challenged with terbinafine or azoles at sub-MIC levels [18,19]. Compounding the evolution of resistance, the spread of these resistant strains could be linked to international travel [61], person-to-person contact [62], and a congregate living setting [63]. This situation is reminiscent of the intercontinental spread of C. auris [60], suggesting that the global spread to resistant Trichophyton species is a distinct possibility.

Tackling these issues will require ongoing surveillance efforts and implementation of antifungal stewardship programs, which is often met with technical and resource limitations in the case of AFST [10]. Our review of the current literature shows multifaceted molecular resistance mechanisms against commonly used antifungals in Trichophyton spp., most notably are the target enzyme alterations and overexpression as well as drug efflux channels. As our knowledge on the landscape of antifungal resistance mechanisms expands, the advent of advanced molecular diagnostics may help to increase testing accessibility and capacity.

Supporting information

S1 Text. Appendix A, Fig A, and Table A.

https://doi.org/10.1371/journal.ppat.1012913.s001

(DOCX)

References

  1. 1. Pathadka S, Yan VKC, Neoh CF, Al-Badriyeh D, Kong DCM, Slavin MA, et al. Global Consumption Trend of Antifungal Agents in Humans From 2008 to 2018: Data From 65 Middle- and High-Income Countries. Drugs. 2022;82:1193–1205. pmid:35960433
  2. 2. Khurana A, Sharath S, Sardana K, Chowdhary A. Clinico-mycological and therapeutic updates on cutaneous dermatophytic infections in the era of Trichophyton indotineae. J Am Acad Dermatol. 2024;91:315–323.
  3. 3. Berry CZ, Shapiro SI, Dahlen RF. Recurrence of Trichophyton rubrum infection during treatment with griseofulvin. Report of a case. Arch Dermatol. 1960;81:982.
  4. 4. Michaelides P, Rosenthal SA, Sulzberger MB, Witten VH. Trichophyton tonsurans infection resistant to griseofulvin. A case demonstrating clinical and in vitro resistance. Arch Dermatol. 1961;83:988–990.
  5. 5. Mukherjee PK, Leidich SD, Isham N, Leitner I, Ryder NS, Ghannoum MA. Clinical Trichophyton rubrum strain exhibiting primary resistance to terbinafine. Antimicrob Agents Chemother. 2003;47:82–86.
  6. 6. Balci DD, Cetin M. Widespread, chronic, and fluconazole-resistant Trichophyton rubrum infection in an immunocompetent patient. Mycoses. 2008;51:546–548.
  7. 7. Kawasaki M, Anzawa K, Wakasa A, Takeda K, Tanabe H, Mochizuki T, et al. Different genes can result in different phylogenetic relationships in Trichophyton species. Nippon Ishinkin Gakkai Zasshi. 2008;49:311–318. pmid:19001759
  8. 8. Verma S, Madhu R. The Great Indian Epidemic of Superficial Dermatophytosis: An Appraisal. Indian J Dermatol. 2017;62:227–236. pmid:28584364
  9. 9. Kano R, Kimura U, Kakurai M, Hiruma J, Kamata H, Suga Y, et al. Trichophyton indotineae sp. nov.: A New Highly Terbinafine-Resistant Anthropophilic Dermatophyte Species. Mycopathologia. 2020;185:947–958.
  10. 10. Kwizera R, Abdolrasouli A, Garcia-Effron G, Denning DW. Antifungal susceptibility testing: applicability of methods and strategies for improving access in resource-constrained settings. Lancet Infect Dis. 2024. pmid:39305909
  11. 11. Rex JH, Pfaller MA. Has antifungal susceptibility testing come of age? Clin Infect Dis. 2002;35:982–989. pmid:12355386
  12. 12. Caplan AS, Todd GC, Zhu YC, Sikora M, Akoh CC, Jakus J, et al. Clinical Course, Antifungal Susceptibility, and Genomic Sequencing of Trichophyton indotineae. JAMA Dermatol. 2024;12208:1–9.
  13. 13. Haghani I, Babaie M, Hoseinnejad A, Rezaei-Matehkolaei A, Mofarrah R, Yahyazadeh Z, et al. High Prevalence of Terbinafine Resistance Among Trichophyton mentagrophytes/T. interdigitale Species Complex, a Cross-Sectional Study from 2021 to 2022 in Northern Parts of Iran. Mycopathologia. 2024;189.
  14. 14. Ebert A, Monod M, Salamin K, Burmester A, Uhrlaß S, Wiegand C, et al. Alarming India-wide phenomenon of antifungal resistance in dermatophytes: A multicentre study. Mycoses. 2020;63:717–728. pmid:32301159
  15. 15. Yamada T, Yaguchi T, Maeda M, Alshahni MM, Salamin K, Guenova E, et al. Gene Amplification of CYP51B: a New Mechanism of Resistance to Azole Compounds in Trichophyton indotineae. Antimicrob Agents Chemother. 2022:66.
  16. 16. Yamada T, Maeda M, Nagai H, Salamin K, Chang Y-T, Guenova E, et al. Two different types of tandem sequences mediate the overexpression of TinCYP51B in azole-resistant Trichophyton indotineae. Antimicrob Agents Chemother. 2023;67:e0093323.
  17. 17. Kong X, Song G, Mei H, Zheng H, Tang C, de Hoog S, et al. The Domestic Isolation of Terbinafine- and Itraconazole-Resistant Trichophyton indotineae in Chinese Mainland. Mycopathologia. 2023.
  18. 18. Hryncewicz-Gwóźdź A, Kalinowska K, Plomer-Niezgoda E, Bielecki J, Jagielski T. Increase in Resistance to Fluconazole and Itraconazole in Trichophyton rubrum Clinical Isolates by Sequential Passages In Vitro under Drug Pressure. Mycopathologia. 2013;176:49–55.
  19. 19. Kano R, Nojo H, Noguchi H. Genomic Analysis of Antifungal Drug Resistance Induced in Trichophyton rubrum After Prolonged Culture with Terbinafine. Mycopathologia. 2023;188:1079–1083.
  20. 20. Martinez-Rossi NM, Peres NTA, Bitencourt TA, Martins MP, Rossi A. State-of-the-Art Dermatophyte Infections: Epidemiology Aspects, Pathophysiology, and Resistance Mechanisms. J Fungi. 2021;7:629. pmid:34436168
  21. 21. Zhang W, Yu L, Yang J, Wang L, Peng J, Jin Q. Transcriptional profiles of response to terbinafine in Trichophyton rubrum. Appl Microbiol Biotechnol. 2009;82:1123–1130.
  22. 22. Martins MP, Franceschini ACC, Jacob TR, Rossi A, Martinez-Rossi NM. Compensatory expression of multidrug-resistance genes encoding ABC transporters in dermatophytes. J Med Microbiol. 2016;65:605–610. pmid:27121717
  23. 23. Peres NT, Sanches PR, Falco JP, Silveira HC, Paião FG, Maranhão FC, et al. Transcriptional profiling reveals the expression of novel genes in response to various stimuli in the human dermatophyte Trichophyton rubrum. BMC Microbiol. 2010:10.
  24. 24. Petrucelli MF, Matsuda JB, Peroni K, Sanches PR, Silva WA, Beleboni RO, et al. The transcriptional profile of Trichophyton rubrum co-cultured with human keratinocytes shows new insights about gene modulation by terbinafine. Pathogens. 2019:8. pmid:31795354
  25. 25. Paião FG, Segato F, Cursino-Santos JR, Peres NTA, Martinez-Rossi NM. Analysis of Trichophyton rubrum gene expression in response to cytotoxic drugs. FEMS Microbiol Lett. 2007;271:180–186.
  26. 26. Fachin AL, Ferreira-Nozawa MS, Maccheroni W, Martinez-Rossi NM. Role of the ABC transporter TruMDR2 in terbinafine, 4-nitroquinoline N-oxide and ethidium bromide susceptibility in Trichophyton rubrum. J Med Microbiol. 2006;55:1093–1099.
  27. 27. Yamada T, Yaguchi T, Tamura T, Pich C, Salamin K, Feuermann M, et al. Itraconazole resistance of Trichophyton rubrum mediated by the ABC transporter TruMDR2. Mycoses. 2021;64:936–946.
  28. 28. Gnat S, Łagowski D, Nowakiewicz A, Dyląg M, Osińska M. Complementary effect of mechanism of multidrug resistance in Trichophyton mentagrophytes isolated from human dermatophytoses of animal origin. Mycoses. 2021;64:537–549.
  29. 29. Kano R. ATP-binding cassette (ABC) transporter proteins in highly terbinafine-resistant strains of Trichophyton indotineae (former species name: Trichophyton interdigitale). Med Mycol J. 2021;62:21–25. pmid:33642524
  30. 30. Yamada T, Yaguchi T, Salamin K, Guenova E, Feuermann M, Monod M. MFS1, a pleiotropic transporter in dermatophytes that plays a key role in their intrinsic resistance to chloramphenicol and fluconazole. J Fungi. 2021;7:1–14. pmid:34356921
  31. 31. Carmo PHF, Costa MC, Leocádio VAT, Gouveia-Eufrásio L, Emídio ECP, Pimentel SP, et al. Exposure to itraconazole influences the susceptibility to antifungals, physiology, and virulence of Trichophyton interdigitale. Med Mycol. 2022:60.
  32. 32. Xiao C, Wang J, Liao Z, Huang Y, Ji Q, Liu Y, et al. Assessment of the mechanism of drug resistance in Trichophyton mentagrophytes in response to various substances. BMC Genomics. 2021;22:250.
  33. 33. Yu L, Zhang W, Wang L, Yang J, Liu T, Peng J, et al. Transcriptional profiles of the response to ketoconazole and amphotericin B in Trichophyton rubrum. Antimicrob Agents Chemother. 2007;51:144–153.
  34. 34. Bhattacharyya A, Sadhasivam S, Sinha M, Gupta S, Saini S, Singh H, et al. Treatment of recalcitrant cases of tinea corporis/cruris caused by T. mentagrophytes—interdigitale complex with mutations in ERG11 ERG 3, ERG4, MDR1 MFS genes & SQLE and their potential implications. Int J Dermatol. 2023 [cited 29 Mar 2023].
  35. 35. Ghelardi E, Celandroni F, Gueye SA, Salvetti S, Senesi S, Bulgheroni A, et al. Potential of ergosterol synthesis inhibitors to cause resistance or cross-resistance in Trichophyton rubrum. Antimicrob Agents Chemother. 2014;58:2825–2829.
  36. 36. Noguchi H, Matsumoto T, Kubo M, Kimura U, Hiruma M, Yaguchi T, et al. Dermatophytoma caused by terbinafine-resistant Trichophyton rubrum treated with fosravuconazole. J Dermatol. 2022;49:e407–e408.
  37. 37. Jacob TR, Peres NTA, Martins MP, Lang EAS, Sanches PR, Rossi A, et al. Heat shock protein 90 (Hsp90) as a molecular target for the development of novel drugs against the dermatophyte Trichophyton rubrum. Front Microbiol. 2015;6:1–10. pmid:26617583
  38. 38. Santos HL, Lang EAS, Segato F, Rossi A, Martinez-Rossi NM. Terbinafine resistance conferred by multiple copies of the salicylate 1-monooxygenase gene in Trichophyton rubrum. Med Mycol. 2018;56:378–381.
  39. 39. Saunte DML, Hare RK, Jørgensen KM, Jørgensen R, Deleuran M, Zachariae CO, et al. Emerging Terbinafine Resistance in Trichophyton: Clinical Characteristics, Squalene Epoxidase Gene Mutations, and a Reliable EUCAST Method for Detection. Antimicrob Agents Chemother. 2019;63:1–9.
  40. 40. Abastabar M, Babaei M, Mohammadi R, Valadan R, Javidnia J, Zaedi A, et al. Iranian National Survey on Tinea Capitis: Antifungal Susceptibility Profile, Epidemiological Characteristics, and Report of Two Strains with a Novel Mutation in SQLE Gene with Homology Modeling. Mycopathologia. 2023;188:449–460.
  41. 41. Winter P, Burmester A, Tittelbach J, Wiegand C. A New Genotype of Trichophyton quinckeanum with Point Mutations in Erg11A Encoding Sterol 14-α Demethylase Exhibits Increased Itraconazole Resistance. J Fungi. 2023:9. pmid:37888261
  42. 42. Burmester A, Hipler UC, Elsner P, Wiegand C. Point mutations in the squalene epoxidase Erg1 and sterol 14-α demethylase Erg11 gene of T. indotineae isolates indicate that the resistant mutant strains evolved independently. Mycoses. 2022;65:97–102.
  43. 43. Teo JWP, Cheng JWS, Chew KL, Lin RTP. Whole genome characterization of Trichophyton indotineae isolated in Singapore. Med Mycol. 2024;62:1–4.
  44. 44. Gnat S, Łagowski D, Dyląg M, Ptaszyńska A, Nowakiewicz A. Modulation of ERG gene expression in fluconazole-resistant human and animal isolates of Trichophyton verrucosum. Braz J Microbiol. 2021;52:2439–2446.
  45. 45. Perlin MH, Andrews J, Toh SS. Essential letters in the fungal alphabet: ABC and MFS transporters and their roles in survival and pathogenicity. Adv Genet. 2014;85:201–253. pmid:24880736
  46. 46. Gadzalski M, Ciesielska A, Stączek P. Bioinformatic survey of ABC transporters in dermatophytes. Gene. 2016;576:466–475. pmid:26524502
  47. 47. Kano R, Kimura U, Noguchi H, Hiruma M. Clinical Isolate of a Multi-Antifungal-Resistant Trichophyton rubrum. Antimicrob Agents Chemother. 2022:66.
  48. 48. Monod M, Feuermann M, Salamin K, Fratti M, Makino M, Alshahni MM, et al. Trichophyton rubrum Azole Resistance Mediated by a New ABC Transporter, TruMDR3. Antimicrob Agents Chemother. 2019;63:1–19.
  49. 49. Ishii M, Yamada T, Ishikawa K, Ichinose K, Monod M, Ohata S. The Ptk2-Pma1 pathway enhances tolerance to terbinafine in Trichophyton rubrum. Groll AH, editor. Antimicrob Agents Chemother. 2024:68.
  50. 50. Lopes MER, Bitencourt TA, Sanches PR, Martins MP, Oliveira VM, Rossi A, et al. Alternative Splicing in Trichophyton rubrum Occurs in Efflux Pump Transcripts in Response to Antifungal Drugs. J Fungi. 2022:8. pmid:36012866
  51. 51. Yazdanpanah S, Sasanipoor F, Khodadadi H, Rezaei-Matehkolaei A, Jowkar F, Zomorodian K, et al. Quantitative analysis of in vitro biofilm formation by clinical isolates of dermatophyte and antibiofilm activity of common antifungal drugs. Int J Dermatol. 2023;62:120–127.
  52. 52. Brilhante RSN, Correia EEM, Guedes GM de M, de Oliveira JS, Castelo-Branco D de SCM, Cordeiro R de A, et al. In vitro activity of azole derivatives and griseofulvin against planktonic and biofilm growth of clinical isolates of dermatophytes. Mycoses. 2018;61:449–454.
  53. 53. Toukabri N, Corpologno S, Bougnoux ME, El Euch D, Sadfi-Zouaoui N, Simonetti G. In vitro biofilms and antifungal susceptibility of dermatophyte and non-dermatophyte moulds involved in foot mycosis. Mycoses. 2018;61:79–87.
  54. 54. Garcia LM, Costa-Orlandi CB, Bila NM, Vaso CO, Gonçalves LNC, Fusco-Almeida AM, et al. A Two-Way Road: Antagonistic Interaction Between Dual-Species Biofilms Formed by Candida albicans/Candida parapsilosis and Trichophyton rubrum. Front Microbiol. 2020;11:1–15. pmid:33013741
  55. 55. Burkhart CN, Burkhart CG, Gupta AK. Dermatophytoma: Recalcitrance to treatment because of existence of fungal biofilm. J Am Acad Dermatol. 2002;47:629–631. pmid:12271316
  56. 56. Noguchi H, Matsumoto T, Kubo M, Kimura U, Hiruma M, Tanaka M, et al. Effective Response of Dermatophytoma Caused by Terbinafine-Resistant Trichophyton interdigitale Solely to Topical Efinaconazole. Mycopathologia. 2022;187:421–422.
  57. 57. LaFleur MD, Kumamoto CA, Lewis K. Candida albicans biofilms produce antifungal-tolerant persister cells. Antimicrob Agents Chemother. 2006;50:3839–3846.
  58. 58. Ramage G, Bachmann S, Patterson TF, Wickes BL, López-Ribot JL. Investigation of multidrug efflux pumps in relation to fluconazole resistance in Candida albicans biofilms. J Antimicrob Chemother. 2002;49:973–980.
  59. 59. Hay RJ. The Spread of Resistant Tinea and the Ingredients of a Perfect Storm. Dermatology. 2022;238:80–81. pmid:33789286
  60. 60. Lockhart SR, Smith DJ, Gold JAW. Trichophyton indotineae and other terbinafine-resistant dermatophytes in North America. J Clin Microbiol. 2023;61:e0090323.
  61. 61. Abdolrasouli A, Borman AM, Johnson EM, Hay RJ, Arias M. Terbinafine-resistant Trichophyton indotineae causing extensive dermatophytosis in a returning traveller, London, UK. Clin Exp Dermatol. 2024;49:635–637.
  62. 62. Spivack S, Gold JAW, Lockhart SR, Anand P, Quilter LAS, Smith DJ, et al. Potential Sexual Transmission of Antifungal-Resistant Trichophyton indotineae. Emerg Infect Dis. 2024;30:807–809. pmid:38437706
  63. 63. Noguchi H, Matsumoto T, Hiruma M, Kimura U, Kashiwada-Nakamura K, Kubo M, et al. Cluster infection caused by a terbinafine-resistant dermatophyte at a group home: The first case series in Japan. Acta Derm Venereol. 2021;101:10–12. pmid:34515800