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

Abstract

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 Mucor circinelloides encodes eight putative PDR-type transporters. In this study, transcription of the eight pdr genes has been analyzed after azole treatment. Only the pdr1 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 pdr1 deletion mutant, transcript level of pdr2 and pdr6 significantly increased. Deletion of pdr2 and pdr6 was also done to create single and double knock out mutants for the three genes. After deletion of pdr2 and pdr6, growth ability of the mutant strains decreased, while deletion of pdr2 resulted in increased sensitivity against posaconazole, ravuconazole and isavuconazole. Our result suggests that the regulation of the eight pdr genes is interconnected and pdr1 and pdr2 participates in the resistance of the fungus to posaconazole, ravuconazole and isavuconazole.

Construction of Canthaxanthin-Producing Yeast by Combining Spatiotemporal Regulation and Pleiotropic Drug Resistance Engineering

“…Cellular stress caused by membrane storage of carotenoids is another major issue encountered in their heterologous biosynthesis. The pleiotropic drug resistance (PDR) family proteins have been reported to play important roles in the resistance of yeast to various stress conditions. , Moreover, some of the PDR transporters are involved in the transmembrane transport of terpenoids and biofuels. , Transcriptomic analysis found the upregulation of PDR family proteins in engineered strains of S. cerevisiae with high carotenoid production .…”

Black Fungus (Mucormycosis) Research in India during 1998-2021: A Scopus-based Scientometric Analysis

“…Genetic studies are a vital approach to understanding some of the possible mechanisms of azole resistance and may help find out how to overcome resistance and improve the efficacy of antifungal drugs. 28 In addition, such studies also help to understand the virulence of mucormycosis. 29 India occupies the second position after the USA in terms of contribution to global mucormycosis research, the reason why Indian researchers need to shoulder more responsibility in futuristic mucormycosis research such as genetics.…”

Recent Advances and Future Directions in the Understanding of Mucormycosis

“…Another common mechanism of acquired azole resistance involves the upregulation of multidrug transporters ( Cowen et al., 2015 ; Revie et al., 2018 ). Deletion of two out of eight M. lusitanicus genes encoding putative ABC transporters of the pleiotropic drug resistance transporter subfamily only increased slightly the susceptibility to some azoles ( Nagy et al., 2021 ). This small effect in antifungal sensibility could be in part explained by the upregulation of other transporter subfamily members, suggesting that the regulation of these genes are interconnected ( Nagy et al., 2021 ).…”