Characterization of Three Pleiotropic Drug Resistance Transporter Genes and Their Participation in the Azole Resistance of Mucor circinelloides

• Published in: Frontiers in cellular and infection microbiology Vol. 11; p. 660347
• Main Authors: Nagy, Gábor, Kiss, Sándor, Varghese, Rakesh, Bauer, Kitti, Szebenyi, Csilla, Kocsubé, Sándor, Homa, Mónika, Bodai, László, Zsindely, Nóra, Vágvölgyi, Csaba, Papp, Tamás
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 14.04.2021
• Subjects: ABC transporter; Antifungal Agents - pharmacology; azole; Azoles; Cellular and Infection Microbiology; CRISPR-Cas9; Drug Resistance, Fungal; Fungal Proteins; Humans; Microbial Sensitivity Tests; Mucor; pleiotropic drug resistance; pleiotropic drug resistance; ABC transporter; Mucor; CRISPR-Cas9; azole
• ISSN: 2235-2988; 2235-2988
• DOI: 10.3389/fcimb.2021.660347

Mucormycosis is a life-threatening opportunistic infection caused by certain members of the fungal order Mucorales. This infection is associated with high mortality rate, which can reach nearly 100% depending on the underlying condition of the patient. Treatment of mucormycosis is challenging because these fungi are intrinsically resistant to most of the routinely used antifungal agents, such as most of the azoles. One possible mechanism of azole resistance is the drug efflux catalyzed by members of the ATP binding cassette (ABC) transporter superfamily. The pleiotropic drug resistance (PDR) transporter subfamily of ABC transporters is the most closely associated to drug resistance. The genome of encodes eight putative PDR-type transporters. In this study, transcription of the eight genes has been analyzed after azole treatment. Only the showed increased transcript level in response to all tested azoles. Deletion of this gene caused increased susceptibility to posaconazole, ravuconazole and isavuconazole and altered growth ability of the mutant. In the deletion mutant, transcript level of and significantly increased. Deletion of and was also done to create single and double knock out mutants for the three genes. After deletion of and , growth ability of the mutant strains decreased, while deletion of resulted in increased sensitivity against posaconazole, ravuconazole and isavuconazole. Our result suggests that the regulation of the eight genes is interconnected and and participates in the resistance of the fungus to posaconazole, ravuconazole and isavuconazole.