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Itraconazole resistance in Madurella fahalii linked to a distinct homolog of the gene encoding cytochrome P450 14-α sterol demethylase (CYP51)

Summary

A fungal infection called mycetoma caused by Madurella fahalii doesn’t respond to a common antifungal drug called itraconazole. Researchers discovered that this fungus has an extra gene that produces a protein that resists the drug, which isn’t found in a similar fungus that remains susceptible. This finding could help develop better treatments for mycetoma patients in the future.

Background

Madurella fahalii is a causative agent of eumycetoma, a neglected tropical disease. Unlike M. mycetomatis, M. fahalii exhibits resistance to itraconazole, the standard treatment for eumycetoma. The underlying mechanism of this resistance remains unknown.

Objective

To identify and characterize the mechanism of itraconazole resistance in M. fahalii using genome sequencing and genetic engineering approaches. The study aimed to understand how M. fahalii develops resistance to itraconazole and improve treatment strategies.

Results

Two copies of the cyp51A gene were identified in M. fahalii: Mfcyp51A1 (conserved among Madurella species) and Mfcyp51A2 (M. fahalii-specific). Both genes were actively transcribed and upregulated in response to itraconazole. S. cerevisiae transformants expressing Mfcyp51A2 exhibited reduced susceptibility to itraconazole compared to those with Mfcyp51A1.

Conclusion

Itraconazole resistance in M. fahalii is attributed to the presence of an additional CYP51 gene (Mfcyp51A2), which is absent in M. mycetomatis. This study represents the first application of genetic engineering techniques to Madurella species and provides insights for developing more effective treatment strategies.
  • Published in:PLoS Neglected Tropical Diseases,
  • Study Type:Genomic and Molecular Biology Study,
  • Source: 10.1371/journal.pntd.0012623; 40146733
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