<i>Trichophyton indotineae Erg1</i><sup>Ala448Thr</sup> Strain Expressed Constitutively High Levels of Sterol 14-α Demethylase <i>Erg11B</i> mRNA, While Transporter <i>MDR3</i> and <i>Erg11A</i> mRNA Expression Was Induced After Addition of Short Chain Azoles
2024
Nadine Berstecher | Anke Burmester | Deborah Maria Gregersen | Jörg Tittelbach | Cornelia Wiegand
<i>Trichophyton indotineae</i> is an emerging pathogen causing recalcitrant skin infections and exhibiting multiple resistances to azoles and allylamines. Squalene epoxidase <i>erg1</i><sup>Ala448Thr</sup> mutants often show association with azole resistance. RT-PCR gene expression analysis helps to elucidate the connection between ergosterol biosynthesis regulation and efflux control through the activation of multidrug resistance (MDR) and major facilitator superfamily (MFS1) transporters as well as heat shock proteins (HSP). Several <i>T. indotineae</i> isolates demonstrated a heat-dependent increase of <i>Erg11B</i> transcripts combined with downregulation of <i>Erg1</i>, suggesting a protective role for <i>Erg11B</i>. They also showed persistent upregulation of <i>MFS1.</i> The addition of fluconazole or voriconazole induced the expression of <i>Erg11A</i>, <i>MDR3</i> and, to a lesser extent, <i>Erg11B</i> and <i>Erg1</i>. The azole-resistant <i>erg1</i><sup>Ala448Thr</sup> mutant UKJ 476/21 exhibited exceptionally high transcript levels of sterol 14-αdemethylase <i>Erg11B</i>, combined with the inability of HSP60 and HSP90 to respond to increasing growth temperatures. Itraconazole demonstrated similar effects in a few <i>T. indotineae</i> isolates, but terbinafine did not enhance <i>Erg1</i> transcription at all. Overexpression of <i>Erg11B</i> may explain the multiple azole resistance phenotype, whereas <i>Erg11B</i> point mutations are not associated with resistance to azoles used for medical treatment.
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