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

Abstract

Background The T indotineae population shows a high amount of terbinafine resistant isolates based on different point mutations of squalene epoxidase erg1 (ergosterol) gene. A significant proportion of these isolates also show azole resistance. Objectives Elucidation of the molecular mechanism for azole resistance, especially the identification of mutations in the sterol 14‐α demethylase Erg11 genes, which encode for enzymes interacting with azoles. Methods Sequencing of putative Erg11 genes and analysis of phenotypic resistance pattern using a microplate‐laser‐nephelometry‐based growth assay. Results Four different types of Erg11B mutants were detected; two double mutants with Ala230Thr/Asp441Gly, respectively, Ala230/Tyr444His and single mutants with Gly443Glu, Tyr444Cys and Tyr444His. All isolates featured the wild type genotype of Erg11A. All strains demonstrated different combinations of Erg1 and Erg11 genotypes. Conclusion Resistance against terbinafine and azoles developed several times independently within the T indotineae population. The challenge for fungal treatment is, therefore, that species identification is not enough for prediction of therapeutic efficacy of antifungals. In the future, it will also become important to analyse genes involved in resistance mechanisms.

Increasing Terbinafine Resistance in Danish Trichophyton Isolates 2019–2020

“…However, India is also known for a high over-the-counter use of antifungal containing medication and a true higher resistance rate is therefore not unexpected. Of note, a number of Indian isolates that harbour the A448T mutations in the SQLE gene has been reported, which has been hypothesized to elevate azole MICs in conjunction with other mutations, but other resistance mechanisms such as target gene mutations or upregulated efflux pumps may also be involved [13,[33][34][35][36]. The in vitro activity of isavuconazole was comparable to that of voriconazole on a mg/L basis.…”

Gene Amplification of CYP51B : a New Mechanism of Resistance to Azole Compounds in Trichophyton indotineae

“…Several amino acid substitutions of TinCYP51B were recently identified in T. indotineae isolates, including Gly443Glu ( 29 ); however, the Gly443Glu substitution detected in TinCYP51B of strains TIMM20116 , TIMM20118 , and TIMM20119 did not appear to play a role in their low susceptibility to azoles ( Fig. 2 ).…”

Detection of emerging genotypes in Trichophyton mentagrophytes species complex: A proposal for handling biodiversity in dermatophytes

“…It may be questioned whether taxonomic distinction of every clone is meaningful for reasons other than epidemiology. For clinical practice, direct analysis of genes which confer resistance may be a good way forward ( Burmester et al, 2022 ).…”