Itraconazole resistance in Madurella fahalii linked to a distinct homolog of the gene encoding cytochrome P450 14-α sterol demethylase (CYP51).
<h4>Background</h4>Mycetoma is a deep fungal infection caused by several microorganisms, with Madurella mycetomatis being the most common causative agent. Another related species, Madurella fahalii, is also known to cause eumycetoma. However, unlike M. mycetomatis, M. fahalii exhibits re...
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Public Library of Science (PLoS)
2025-03-01
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| Series: | PLoS Neglected Tropical Diseases |
| Online Access: | https://doi.org/10.1371/journal.pntd.0012623 |
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| author | Isato Yoshioka Ahmed Hassan Fahal Satoshi Kaneko Wei Cao Takashi Yaguchi |
| author_facet | Isato Yoshioka Ahmed Hassan Fahal Satoshi Kaneko Wei Cao Takashi Yaguchi |
| author_sort | Isato Yoshioka |
| collection | DOAJ |
| description | <h4>Background</h4>Mycetoma is a deep fungal infection caused by several microorganisms, with Madurella mycetomatis being the most common causative agent. Another related species, Madurella fahalii, is also known to cause eumycetoma. However, unlike M. mycetomatis, M. fahalii exhibits resistance to itraconazole, the standard treatment for eumycetoma, and the underlying cause of this resistance remains unknown. Therefore, understanding the mechanism of this resistance is critical for developing more effective therapies.<h4>Principal findings</h4>Using the high-quality draft genome sequence of Madurella fahalii IFM 68171, we identified two copies of the gene encoding cytochrome P450 14-α sterol demethylase (CYP51), the target enzyme of itraconazole. These include a gene conserved among Madurella species (Mfcyp51A1) and a M. fahalii-specific gene (Mfcyp51A2). Both genes are actively transcribed in M. fahalii and are upregulated in response to itraconazole. Furthermore, heterologous expression in Saccharomyces cerevisiae revealed that transformants carrying the Mfcyp51A2 gene exhibited reduced susceptibility to itraconazole compared to those with Mfcyp51A1.<h4>Conclusion</h4>We demonstrated that itraconazole resistance in M. fahalii may be attributed to the presence of an additional CYP51 gene. This study represents the first report on the physiological characteristics of Madurella species using genetic engineering techniques. |
| format | Article |
| id | doaj-art-5540e291f3db4deba724f06d7ce8774c |
| institution | OA Journals |
| issn | 1935-2727 1935-2735 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Neglected Tropical Diseases |
| spelling | doaj-art-5540e291f3db4deba724f06d7ce8774c2025-08-20T02:12:19ZengPublic Library of Science (PLoS)PLoS Neglected Tropical Diseases1935-27271935-27352025-03-01193e001262310.1371/journal.pntd.0012623Itraconazole resistance in Madurella fahalii linked to a distinct homolog of the gene encoding cytochrome P450 14-α sterol demethylase (CYP51).Isato YoshiokaAhmed Hassan FahalSatoshi KanekoWei CaoTakashi Yaguchi<h4>Background</h4>Mycetoma is a deep fungal infection caused by several microorganisms, with Madurella mycetomatis being the most common causative agent. Another related species, Madurella fahalii, is also known to cause eumycetoma. However, unlike M. mycetomatis, M. fahalii exhibits resistance to itraconazole, the standard treatment for eumycetoma, and the underlying cause of this resistance remains unknown. Therefore, understanding the mechanism of this resistance is critical for developing more effective therapies.<h4>Principal findings</h4>Using the high-quality draft genome sequence of Madurella fahalii IFM 68171, we identified two copies of the gene encoding cytochrome P450 14-α sterol demethylase (CYP51), the target enzyme of itraconazole. These include a gene conserved among Madurella species (Mfcyp51A1) and a M. fahalii-specific gene (Mfcyp51A2). Both genes are actively transcribed in M. fahalii and are upregulated in response to itraconazole. Furthermore, heterologous expression in Saccharomyces cerevisiae revealed that transformants carrying the Mfcyp51A2 gene exhibited reduced susceptibility to itraconazole compared to those with Mfcyp51A1.<h4>Conclusion</h4>We demonstrated that itraconazole resistance in M. fahalii may be attributed to the presence of an additional CYP51 gene. This study represents the first report on the physiological characteristics of Madurella species using genetic engineering techniques.https://doi.org/10.1371/journal.pntd.0012623 |
| spellingShingle | Isato Yoshioka Ahmed Hassan Fahal Satoshi Kaneko Wei Cao Takashi Yaguchi Itraconazole resistance in Madurella fahalii linked to a distinct homolog of the gene encoding cytochrome P450 14-α sterol demethylase (CYP51). PLoS Neglected Tropical Diseases |
| title | Itraconazole resistance in Madurella fahalii linked to a distinct homolog of the gene encoding cytochrome P450 14-α sterol demethylase (CYP51). |
| title_full | Itraconazole resistance in Madurella fahalii linked to a distinct homolog of the gene encoding cytochrome P450 14-α sterol demethylase (CYP51). |
| title_fullStr | Itraconazole resistance in Madurella fahalii linked to a distinct homolog of the gene encoding cytochrome P450 14-α sterol demethylase (CYP51). |
| title_full_unstemmed | Itraconazole resistance in Madurella fahalii linked to a distinct homolog of the gene encoding cytochrome P450 14-α sterol demethylase (CYP51). |
| title_short | Itraconazole resistance in Madurella fahalii linked to a distinct homolog of the gene encoding cytochrome P450 14-α sterol demethylase (CYP51). |
| title_sort | itraconazole resistance in madurella fahalii linked to a distinct homolog of the gene encoding cytochrome p450 14 α sterol demethylase cyp51 |
| url | https://doi.org/10.1371/journal.pntd.0012623 |
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