Roles of Pleiotropic Drug Resistance (PdR) Genes in Azole Resistance in a Pathogenic Mucorales, Mucor circinelloides

Date

2019

Authors

Turner, Broderick

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Abstract

Mucormycosis is a life-threatening opportunistic infection caused by fungi of the order Mucorales, including but not limited to the genera Rhizopus, Mucor, and Rhizomucor. It is seen predominantly in severely immunocompromised individuals and susceptible cohorts include patients with hematological malignancies, diabetic ketoacidosis, or solid organ transplant. Infections occur in the lungs, rhinocerebral spaces, GI tract, and traumatic lesions in soft tissues. In addition to its broad tissue tropism the mortality rate is as high as 90% once disseminated to the brain with limited treatment options. Azoles are antifungal agents that prevent the synthesis of ergosterol, a major component of fungal plasma membranes. However, it is well known that Mucorales fungi harbor intrinsic resistance to majority of azole drugs. The goal of this project is to characterize the effect of M. circinelloides pdr (pleotropic drug resistance, pdrA to pdrH) genes potential roles in the intrinsic azole resistance. A significant upregulation in pdrC gene expression among 8 pdr genes were observed when the wildtype strain is challenged with the azoles, fluconazole, voriconazole, isavuconazole, and posaconazole. The phylogenetic analysis showed that pdrC is closely related to the pdrA and pdrB genes. We therefore generated pdrABCΔ triple deletion mutants to test roles of this group of the pdr genes. The MIC data we obtained using a checkerboard assay however revealed no significant increase in susceptibility to azoles in these mutants compared to wildtype. Interestingly, we observed a significant upregulation of pdrH when the pdrABCΔ mutant strain is challenged with the azoles, indicating that the absence of pdrA, pdrB, and pdrC was compensated by overexpression of the pdrH gene. These results suggest that the pdr genes of M. circinelloides may operate in a redundant manner to confer the azole resistance phenotype seen in this organism. Construction of pdrABCH quadruple deletion mutants and drug resistance phenotype analysis are underway to further test our hypothesis.

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Keywords

azole, fungi, mucor, pdr, resistance

Citation

Department

Integrative Biology