Models of the proteins produced by Madurella fahalii: CYP51A (A and C) and CYP51A2 (B and D). In each panel, itraconazole and heme are illustrated in a stick representation in the upper and lower parts, respectively. (A) and (B) represent the overall structure of CYP51 proteins. In (C) and (D), the active centers of (A) and (B) were enlarged with their protein backbones made translucent, respectively.
Image credit: Takashi Yaguchi
Investigators have identified the mechanism behind drug resistance for treating mycetoma caused by Madurella fahalii. Mycetoma can be a severe, chronic disease and is frequently drug-resistant to standard treatment with itraconazole when it is caused by this particular fungus. 1
The mechanism of resistance is an additional gene encoding a variant of cytochrome P450 14-α sterol demethylase. Using genetic engineering, protein modeling, and computer simulations, the Chiba team demonstrated how this second gene reduces treatment effectiveness, guiding the development of future effective therapies.1 The study was published in PLOS Neglected Tropical Diseases.
To treat the fungal form of mycetoma, known as eumycetoma, clinicians have typically used itraconazole—an antifungal medication that targets a key fungal enzyme. However, when the disease is caused by Madurella fahalii, a lesser-known fungal species, this has often shown resistance to itraconazole, leaving patients with few treatment alternatives. Until recently, the reasons behind this resistance remained poorly understood.1
This new research included different universities and was led by associate professor Takashi Yaguchi, PhD, the Medical Mycology Research Center, Chiba University. Together, they investigated the molecular mechanisms behind itraconazole resistance in M fahalii.
Using genome sequencing and genetic engineering techniques, the researchers identified that, unlike its treatable cousin M mycetomatis, M fahalii possesses an additional gene encoding the enzyme cytochrome P450 14-α sterol demethylase (CYP51). This second copy of the M fahalii-specific gene (Mfcyp51A2), which encodes the specific target of itraconazole, has key functional and structural differences compared to the gene common with M mycetomatis (Mfcyp51A1), effectively neutralizing the drug’s impact.1
The team confirmed their discovery through multiple approaches. They demonstrated that both copies of the gene become more active when the fungus is exposed to itraconazole, with the unique Mfcyp51A2 gene showing particularly strong activation—a typical defensive response. When the researchers transplanted these genes into yeast cells for further testing, cells carrying the Mfcyp51A2 gene were markedly less susceptible to itraconazole compared to those with the standard gene version.
About Mycetoma
According to the Centers for Disease Control and Prevention (CDC), mycetoma is a chronic, progressive subcutaneous skin infection that can be caused by bacteria or fungi.2 Characterized by painful swelling, skin nodules, and pus-discharging sinuses, the condition primarily affects individuals who come into frequent contact with soil, such as agricultural and manual workers. Despite its serious health and socioeconomic consequences, mycetoma has been largely overlooked by global medical research, resulting in limited diagnostic tools and few effective treatment options.1 If left untreated, mycetoma can spread into tissues or bone and can lead to disability. And in some cases, lead to amputation.2
Mycetoma affects thousands of people living in tropical and subtropical regions, particularly those in low-resource settings.1 CDC says it primarily affects low-income agrarian populations in tropical regions. Endemic countries are called the Mycetoma Belt and include Venezuela, Chad, Ethiopia, India, Mauritania, Mexico, Senegal, Somalia, Sudan, and Yemen. 2
Not much is known about mycetoma’s transmission, risk factors, or pathogenesis.
CDC explains that mycetoma is caused by a diverse group of microorganisms. The predominant etiologic agent varies by geographic region. Fungal mycetoma (eumycetoma) and bacterial mycetoma (actinomycetoma) cause disease in Africa and Asia, while bacterial mycetoma (actinomycetoma) causes the majority of cases in South and Central America. 2
In 2016, the World Health Organization added mycetoma to its list of neglected tropical diseases, which is a significant step to better understand the disease and to establish prevention recommendations, and to improve upon diagnostics and therapies for it.2
This research marks a significant step forward in addressing a severe disease that primarily affects impoverished communities. By understanding how drug resistance develops at the molecular level, scientists can work on targeted approaches to overcome it. “Our findings will hopefully pave the way for more effective treatment strategies for eumycetoma caused by M fahalii in the future,” Yaguchi said in a statement.
References
1.Uncovering the Shield: Gene Duplication Behind Antifungal Resistance in Madurella fahalii. Chiba University. May 22, 2025. Accessed May 26, 2025.
2.Clinical Overview of Mycetoma. CDC. April 24, 2024. Accessed May 26, 2025.
https://www.cdc.gov/mycetoma/hcp/clinical-overview/index.html
