Gene Duplication in Fungus Causes Resistance, Hindering Treatment of Tropical Mycetoma

Mycetoma is a chronic infectious disease prevalent in tropical and subtropical regions, mainly affecting impoverished communities engaged in agriculture or manual labor. Characterized by painful swelling, skin nodules, and discharging sinuses, the disease can lead to severe disfigurement and disability if untreated. Despite its significant health impact, mycetoma has historically received limited attention from global health research, resulting in few effective diagnostic and treatment options.

The fungal form of mycetoma, called eumycetoma, is commonly treated with itraconazole, an antifungal drug that targets a specific enzyme essential for the fungus's survival. However, resistant cases caused by Madurella fahalii have emerged, leaving many patients without effective therapies. Until recently, the underlying mechanisms for this resistance remained unclear.

A team led by Associate Professor Takashi Yaguchi from the Medical Mycology Research Center at Chiba University conducted a detailed investigation into the molecular basis of itraconazole resistance in M. fahalii. Their study, published on March 27, 2025, in PLOS Neglected Tropical Diseases, utilized advanced genetic and biochemical techniques to uncover how this fungus evades the drug.

The researchers discovered that M. fahalii possesses an additional gene encoding the enzyme cytochrome P450 14-α sterol demethylase (CYP51). This secondary gene, called Mfcyp51A2, shares structural and functional differences from the version found in treatable species like M. mycetomatis. Notably, Mfcyp51A2 is highly activated when the fungus is exposed to itraconazole, acting as a defensive response that reduces the drug's effectiveness.

Genetic experiments involving yeast cells revealed that the Mfcyp51A2 gene makes the fungus less susceptible to itraconazole. The enzyme produced by this gene binds the drug weakly, thereby diminishing the drug's ability to inhibit fungal growth. Consequently, the duplication and activation of this gene confer resistance to M. fahalii.

This research marks a major advancement by being the first to elucidate the genetic resistance mechanisms in Madurella species through molecular engineering. It highlights the potential of using genetic insights to develop novel strategies for overcoming drug resistance in neglected fungal pathogens.

Understanding the molecular basis of itraconazole resistance allows scientists to explore targeted therapies that can bypass or inhibit the resistant gene. Such innovations could greatly improve treatment outcomes for mycetoma, especially in resource-limited regions where the disease persists. As Dr. Yaguchi emphasizes, "Our findings open avenues for developing more effective treatments for M. fahalii-induced mycetoma."

Overall, this study underscores the importance of basic science research in solving real-world health problems. By dissecting resistance at the genetic level, researchers lay the groundwork for next-generation antifungal therapies that could mitigate the burden of mycetoma globally.