Indian <i>Trichophyton mentagrophytes</i> squalene epoxidase <i>erg1</i> double mutants show high proportion of combined fluconazole and terbinafine resistance

Burmester, Anke; Hipler, Uta‐Christina; Uhrlaß, Silke; Nenoff, P.; Singal, Archana; Verma, Shyam; Elsner, Peter; Wiegand, Cornelia

doi:10.1111/myc.13150

Cited by 31 publications

(51 citation statements)

References 14 publications

(28 reference statements)

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“…In Trichophyton rubrum, nucleotide substitution occurred at 1380, leading to the replacement of CAT with TAT 8 . Another substitution occurred at 1175 position leading to the replacement of TTC by TTA that was near related to previous study 21 in which the nucleotide and amino acid substitution in the squalene epoxidase gene varies between homologs of the Trichophyton group.…”

Section: Single Nucleotide Polymorphisms (Snps) In Squalene Epoxidase Genesupporting

confidence: 85%

Metadata analysis of the squalene epoxidase gene in dermatophytes

Ismail¹,

Ahmad²,

Javed³

2021

Int. j. endorsing health sci. res.

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Background: Squalene epoxidase gene is an azole antifungal target enzyme in the ergosterol biosynthesis pathway in fungi-the inhibition of enzyme aggregate squalene, a type of ergosterol derivative depletion that leads to fungal growth inhibition. Squalene epoxidase widely diverges in three fungal groups of dermatophytes Trichophyton, Microsporum and Epidermophyton. Methodology:The study has demonstrated a variety of squalene epoxidase genes in the dermatophyte genome. Squalene epoxidase gene was also studied for possible single nucleotide polymorphism (SNPs) in the Trichophyton group's homologs and found multiple SNP positions that induce non-synonymous mutation and change the sequence of amino acid into protein structure that can change phenylalanine to leucine. Results: Squalene epoxidase is widely present in dermatophytes. Mutation in the squalene epoxidase gene can mislead normal sterol formation in the fungal cell membrane that induces fungal resistance against several drugs, including azoles and polyenes. Squalene epoxidase gene carries 2 -3 transcripts and 2 -3 number of exons. Squalene epoxidase gene has FAD-dependent oxidoreductases and NADP binding domain conserved domains in fungal groups of dermatophytes. Conclusion:This study analyzed the abundance of the squalene epoxidase gene, suggesting that squalene epoxidase gene resistant mutants can occur naturally. Thus squalene epoxidase gene should be extensively studied in order to increase the potential of available antifungals.

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Section: Single Nucleotide Polymorphisms (Snps) In Squalene Epoxidase Genesupporting

confidence: 85%

Metadata analysis of the squalene epoxidase gene in dermatophytes

Ismail¹,

Ahmad²,

Javed³

2021

Int. j. endorsing health sci. res.

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“…Remarkably, three out of four strains showing resistance to voriconazole were also resistant to itraconazole, strengthening evidence that these strains share a common mechanism of resistance against triazoles [ 15 ]. Triazole resistance was recently associated with the substitution Ala 448 Thr in squalene epoxidase [ 15 , 30 ] and such a tendency could be observed in the current collection of strains. However, statistical significance could not be proven due to the relatively small sample size.…”

Section: Discussionmentioning

confidence: 97%

“…mentagrophytes / T . interdigitale complex [ 16 , 21 , 25 , 26 , 27 , 28 , 29 , 30 ] ( Figure 5 a–d). Therefore, it does not appear justifiable to attempt assigning this single genotype VIII of T .…”

Section: Discussionmentioning

confidence: 99%

“…However, statistical significance could not be proven due to the relatively small sample size. Further investigations, especially on the role of SQLE double mutants on antifungal susceptibility [ 30 ], need to be carried out.…”

Section: Discussionmentioning

confidence: 99%

“…T. mentagrophytes Type VIII is only one variety within the cluster of a large number of genotypes of the T. mentagrophytes/T. interdigitale complex [16,21,[25][26][27][28][29][30] (Figure 5a-d). Therefore, it does not appear justifiable to attempt assigning this single genotype VIII of T. mentagrophytes to a brand new species, so hurriedly, on the basis of just two isolated terbinafine-resistance isolates of T. mentagrophytes, disregarding the plethora of literature on a well-accepted taxonomy and nuances of this genotype, as has just happened in an isolated publication from Japan [31].…”

Section: Trichophyton Mentagrophytes Type VIII (India)mentioning

confidence: 99%

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Spread of Terbinafine-Resistant Trichophyton mentagrophytes Type VIII (India) in Germany–“The Tip of the Iceberg?”

Nenoff¹,

Verma²,

Ebert

et al. 2020

JoF

Self Cite

127

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Chronic recalcitrant dermatophytoses, due to Trichophyton (T.) mentagrophytes Type VIII are on the rise in India and are noteworthy for their predominance. It would not be wrong to assume that travel and migration would be responsible for the spread of T. mentagrophytes Type VIII from India, with many strains resistant to terbinafine, to other parts of the world. From September 2016 until March 2020, a total of 29 strains of T. mentagrophytes Type VIII (India) were isolated. All patients were residents of Germany: 12 females, 15 males and the gender of the remaining two was not assignable. Patients originated from India (11), Pakistan (two), Bangladesh (one), Iraq (two), Bahrain (one), Libya (one) and other unspecified countries (10). At least two patients were German-born residents. Most samples (21) were collected in 2019 and 2020. All 29 T. mentagrophytes isolates were sequenced (internal transcribed spacer (ITS) and translation elongation factor 1-α gene (TEF1-α)). All were identified as genotype VIII (India) of T. mentagrophytes. In vitro resistance testing revealed 13/29 strains (45%) to be terbinafine-resistant with minimum inhibitory concentration (MIC) breakpoints ≥0.2 µg/mL. The remaining 16 strains (55%) were terbinafine-sensitive. Point mutation analysis revealed that 10/13 resistant strains exhibited Phe397Leu amino acid substitution of squalene epoxidase (SQLE), indicative for in vitro resistance to terbinafine. Two resistant strains showed combined Phe397Leu and Ala448Thr amino acid substitutions, and one strain a single Leu393Phe amino acid substitution. Out of 16 terbinafine-sensitive strains, in eight Ala448Thr, and in one Ala448Thr +, new Val444 Ile amino acid substitutions were detected. Resistance to both itraconazole and voriconazole was observed in three out of 13 analyzed strains. Treatment included topical ciclopirox olamine plus topical miconazole or sertaconazole. Oral itraconazole 200 mg twice daily for four to eight weeks was found to be adequate. Terbinafine-resistant T. mentagrophytes Type VIII are being increasingly isolated. In Germany, transmission of T. mentagrophytes Type VIII from the Indian subcontinent to Europe should be viewed as a significant public health issue.

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Efficacy of antifungal agents against fungal spores: An in vitro study using microplate laser nephelometry and an artificially infected 3D skin model

et al. 2022

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Dermal fungal infections seem to have increased over recent years. There is further a shift from anthropophilic dermatophytes to a growing prevalence of zoophilic species and the emergence of resistant strains. New antifungals are needed to combat these fungi and their resting spores. This study aimed to investigate the sporicidal effects of sertaconazole nitrate using microplate laser nephelometry against the microconidia of Trichophyton , chlamydospores of Epidermophyton , blastospores of Candida , and conidia of the mold Scopulariopsis brevicaulis . The results obtained were compared with those from ciclopirox olamine and terbinafine. The sporicidal activity was further determined using infected three‐dimensional full skin models to determine the antifungal effects in the presence of human cells. Sertaconazole nitrate inhibited the growth of dermatophytes, molds, and yeasts. Ciclopirox olamine also had good antifungal activity, although higher concentrations were needed compared to sertaconazole nitrate. Terbinafine was highly effective against most dermatophytes, but higher concentrations were required to kill the resistant strain Trichophyton indotineae . Sertaconazole nitrate, ciclopirox olamine, and terbinafine had no negative effects on full skin models. Sertaconazole nitrate reduced the growth of fungal and yeast spores over 72 h. Ciclopirox olamine and terbinafine also inhibited the growth of dermatophytes and molds but had significantly lower effects on the yeast. Sertaconazole nitrate might have advantages over the commonly used antifungals ciclopirox olamine and terbinafine in combating resting spores, which persist in the tissues, and thus in the therapy of recurring dermatomycoses.

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Indian Trichophyton mentagrophytes squalene epoxidase erg1 double mutants show high proportion of combined fluconazole and terbinafine resistance

Cited by 31 publications

References 14 publications

Metadata analysis of the squalene epoxidase gene in dermatophytes

Metadata analysis of the squalene epoxidase gene in dermatophytes

Spread of Terbinafine-Resistant Trichophyton mentagrophytes Type VIII (India) in Germany–“The Tip of the Iceberg?”

Efficacy of antifungal agents against fungal spores: An in vitro study using microplate laser nephelometry and an artificially infected 3D skin model

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