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

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 becaus...

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Published inFrontiers 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
LanguageEnglish
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
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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 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.
AbstractList 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.
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.
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.
Author Homa, Mónika
Zsindely, Nóra
Nagy, Gábor
Szebenyi, Csilla
Varghese, Rakesh
Papp, Tamás
Vágvölgyi, Csaba
Kocsubé, Sándor
Bodai, László
Kiss, Sándor
Bauer, Kitti
AuthorAffiliation 1 Department of Microbiology, Faculty of Science and Informatics, University of Szeged , Szeged , Hungary
2 MTA-SZTE “Lendület” Fungal Pathogenicity Mechanisms Research Group, Department of Microbiology, University of Szeged , Szeged , Hungary
3 Department of Biochemistry and Molecular Biology, Faculty of Science and Informatics, University of Szeged , Szeged , Hungary
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Copyright Copyright © 2021 Nagy, Kiss, Varghese, Bauer, Szebenyi, Kocsubé, Homa, Bodai, Zsindely, Nagy, Vágvölgyi and Papp.
Copyright © 2021 Nagy, Kiss, Varghese, Bauer, Szebenyi, Kocsubé, Homa, Bodai, Zsindely, Nagy, Vágvölgyi and Papp 2021 Nagy, Kiss, Varghese, Bauer, Szebenyi, Kocsubé, Homa, Bodai, Zsindely, Nagy, Vágvölgyi and Papp
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Keywords pleiotropic drug resistance
ABC transporter
Mucor
CRISPR-Cas9
azole
Language English
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Snippet Mucormycosis is a life-threatening opportunistic infection caused by certain members of the fungal order Mucorales. This infection is associated with high...
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SubjectTerms 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
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Title Characterization of Three Pleiotropic Drug Resistance Transporter Genes and Their Participation in the Azole Resistance of Mucor circinelloides
URI https://www.ncbi.nlm.nih.gov/pubmed/33937100
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