A New Variant of Mutational and Polymorphic Signatures in the ERG11 Gene of Fluconazole-Resistant Candida albicans
Arome Solomon Odiba,1,2 Olanrewaju Ayodeji Durojaye,3– 5 Ifeoma Maureen Ezeonu,6 Anthony Christian Mgbeahuruike,7 Bennett Chima Nwanguma1,2 1Department of Biochemistry, Faculty of Biological Sciences, University of Nigeria, Nsukka, Enugu State, 410001, Nigeria; 2Department of Molecular Genetics and...
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| Language: | English |
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Dove Medical Press
2022-06-01
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| Series: | Infection and Drug Resistance |
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| Online Access: | https://www.dovepress.com/a-new-variant-of-mutational-and-polymorphic-signatures-in-the-erg11-ge-peer-reviewed-fulltext-article-IDR |
| _version_ | 1818253310231052288 |
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| author | Odiba AS Durojaye OA Ezeonu IM Mgbeahuruike AC Nwanguma BC |
| author_facet | Odiba AS Durojaye OA Ezeonu IM Mgbeahuruike AC Nwanguma BC |
| author_sort | Odiba AS |
| collection | DOAJ |
| description | Arome Solomon Odiba,1,2 Olanrewaju Ayodeji Durojaye,3– 5 Ifeoma Maureen Ezeonu,6 Anthony Christian Mgbeahuruike,7 Bennett Chima Nwanguma1,2 1Department of Biochemistry, Faculty of Biological Sciences, University of Nigeria, Nsukka, Enugu State, 410001, Nigeria; 2Department of Molecular Genetics and Biotechnology, University of Nigeria, Nsukka, Enugu State, 410001, Nigeria; 3Department of Chemical Sciences, Coal City University, Emene, Enugu State, Nigeria; 4Department of Molecular and Cell Biology, University of Science and Technology of China, Hefei, Anhui, 230026, People’s Republic of China; 5MOE Key Laboratory of Membraneless Organelle and Cellular Dynamics, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China; 6Department of Microbiology, Faculty of Biological Sciences, University of Nigeria, Nsukka, Enugu State, 410001, Nigeria; 7Department of Veterinary Pathology and Microbiology, Faculty of Veterinary Medicine, University of Nigeria, Nsukka, Enugu State, 410001, NigeriaCorrespondence: Bennett Chima Nwanguma; Anthony Christian Mgbeahuruike, Department of Biochemistry, Faculty of Biological Sciences, University of Nigeria, Enugu State, Nsukka, 410001, Nigeria, Tel +234 8063655062, Email bennett.nwanguma@unn.edu.ng; anthony.mgbeahuruike@unn.edu.ngBackground: Resistance to antifungal drugs for treating Candida infections remains a major concern globally despite the range of medications available. Most of these drugs target key proteins essential to the life cycle of the organism. An enzyme essential for fungal cell membrane integrity, lanosterol 14–α demethylase (CYP51), is encoded by the ERG11 gene in Candida species. This enzyme is the target of azole–based drugs. The organism has, however, devised molecular adaptations to evade the activity of these drugs.Materials and Methods: Classical methods were employed to characterize clinical isolates sampled from women and dogs of reproductive age. For fluconazole efficacy studies, CLSI guidelines on drug susceptibility testing were used. To understand the susceptibility pattern, various molecular and structural analytic approaches, including sequencing, in silico site-directed mutagenesis, and protein-ligand profiling, were applied to the ERG11 gene and CYP51 protein sequences. Several platforms, comprising Clustal Omega, Pymol plugin manager, Pymol molecular visualizer, Chimera–curated Dynameomics rotamer library, protein–ligand interaction profiler, Charmm36 force field, GROMACS, Geneious, and Mega7, were employed for this analysis.Results: The following Candida species distribution was obtained: 37.84% C. albicans, 8.12% C. glabrata, 10.81% C. krusei, 5.41% C. tropicalis, and 37.84% of other unidentified Candida species. Two codons in the nucleotide sequence of the wild-type (CTC and CCA) coding for LEU– 370 and PRO– 375, respectively, were mutated to L370S and P375H in the resistant strain. The mutation stabilized the protein at the expense of the heme moiety. We found that the susceptible isolate from dogs (Can–iso– 029/dog) is closely related to the most resistant isolate from humans.Conclusion: Taken together, our results showed new mutations in the heme-binding pocket of caCYP51 that explain the resistance to fluconazole exhibited by the Candida isolates. So far, the L370S and P375H resistance-linked mutations have not been previously reported.Keywords: Candida infection, CYP51, drug resistance, ERG11, fluconazole, mutation |
| first_indexed | 2024-12-12T16:38:02Z |
| format | Article |
| id | doaj.art-d824e124baa54056909c09ae7ef44ebd |
| institution | Directory Open Access Journal |
| issn | 1178-6973 |
| language | English |
| last_indexed | 2024-12-12T16:38:02Z |
| publishDate | 2022-06-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | Infection and Drug Resistance |
| spelling | doaj.art-d824e124baa54056909c09ae7ef44ebd2022-12-22T00:18:37ZengDove Medical PressInfection and Drug Resistance1178-69732022-06-01Volume 153111313375999A New Variant of Mutational and Polymorphic Signatures in the ERG11 Gene of Fluconazole-Resistant Candida albicansOdiba ASDurojaye OAEzeonu IMMgbeahuruike ACNwanguma BCArome Solomon Odiba,1,2 Olanrewaju Ayodeji Durojaye,3– 5 Ifeoma Maureen Ezeonu,6 Anthony Christian Mgbeahuruike,7 Bennett Chima Nwanguma1,2 1Department of Biochemistry, Faculty of Biological Sciences, University of Nigeria, Nsukka, Enugu State, 410001, Nigeria; 2Department of Molecular Genetics and Biotechnology, University of Nigeria, Nsukka, Enugu State, 410001, Nigeria; 3Department of Chemical Sciences, Coal City University, Emene, Enugu State, Nigeria; 4Department of Molecular and Cell Biology, University of Science and Technology of China, Hefei, Anhui, 230026, People’s Republic of China; 5MOE Key Laboratory of Membraneless Organelle and Cellular Dynamics, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China; 6Department of Microbiology, Faculty of Biological Sciences, University of Nigeria, Nsukka, Enugu State, 410001, Nigeria; 7Department of Veterinary Pathology and Microbiology, Faculty of Veterinary Medicine, University of Nigeria, Nsukka, Enugu State, 410001, NigeriaCorrespondence: Bennett Chima Nwanguma; Anthony Christian Mgbeahuruike, Department of Biochemistry, Faculty of Biological Sciences, University of Nigeria, Enugu State, Nsukka, 410001, Nigeria, Tel +234 8063655062, Email bennett.nwanguma@unn.edu.ng; anthony.mgbeahuruike@unn.edu.ngBackground: Resistance to antifungal drugs for treating Candida infections remains a major concern globally despite the range of medications available. Most of these drugs target key proteins essential to the life cycle of the organism. An enzyme essential for fungal cell membrane integrity, lanosterol 14–α demethylase (CYP51), is encoded by the ERG11 gene in Candida species. This enzyme is the target of azole–based drugs. The organism has, however, devised molecular adaptations to evade the activity of these drugs.Materials and Methods: Classical methods were employed to characterize clinical isolates sampled from women and dogs of reproductive age. For fluconazole efficacy studies, CLSI guidelines on drug susceptibility testing were used. To understand the susceptibility pattern, various molecular and structural analytic approaches, including sequencing, in silico site-directed mutagenesis, and protein-ligand profiling, were applied to the ERG11 gene and CYP51 protein sequences. Several platforms, comprising Clustal Omega, Pymol plugin manager, Pymol molecular visualizer, Chimera–curated Dynameomics rotamer library, protein–ligand interaction profiler, Charmm36 force field, GROMACS, Geneious, and Mega7, were employed for this analysis.Results: The following Candida species distribution was obtained: 37.84% C. albicans, 8.12% C. glabrata, 10.81% C. krusei, 5.41% C. tropicalis, and 37.84% of other unidentified Candida species. Two codons in the nucleotide sequence of the wild-type (CTC and CCA) coding for LEU– 370 and PRO– 375, respectively, were mutated to L370S and P375H in the resistant strain. The mutation stabilized the protein at the expense of the heme moiety. We found that the susceptible isolate from dogs (Can–iso– 029/dog) is closely related to the most resistant isolate from humans.Conclusion: Taken together, our results showed new mutations in the heme-binding pocket of caCYP51 that explain the resistance to fluconazole exhibited by the Candida isolates. So far, the L370S and P375H resistance-linked mutations have not been previously reported.Keywords: Candida infection, CYP51, drug resistance, ERG11, fluconazole, mutationhttps://www.dovepress.com/a-new-variant-of-mutational-and-polymorphic-signatures-in-the-erg11-ge-peer-reviewed-fulltext-article-IDRcandida infectioncyp51drug resistanceerg11fluconazolemutation |
| spellingShingle | Odiba AS Durojaye OA Ezeonu IM Mgbeahuruike AC Nwanguma BC A New Variant of Mutational and Polymorphic Signatures in the ERG11 Gene of Fluconazole-Resistant Candida albicans Infection and Drug Resistance candida infection cyp51 drug resistance erg11 fluconazole mutation |
| title | A New Variant of Mutational and Polymorphic Signatures in the ERG11 Gene of Fluconazole-Resistant Candida albicans |
| title_full | A New Variant of Mutational and Polymorphic Signatures in the ERG11 Gene of Fluconazole-Resistant Candida albicans |
| title_fullStr | A New Variant of Mutational and Polymorphic Signatures in the ERG11 Gene of Fluconazole-Resistant Candida albicans |
| title_full_unstemmed | A New Variant of Mutational and Polymorphic Signatures in the ERG11 Gene of Fluconazole-Resistant Candida albicans |
| title_short | A New Variant of Mutational and Polymorphic Signatures in the ERG11 Gene of Fluconazole-Resistant Candida albicans |
| title_sort | new variant of mutational and polymorphic signatures in the erg11 gene of fluconazole resistant candida albicans |
| topic | candida infection cyp51 drug resistance erg11 fluconazole mutation |
| url | https://www.dovepress.com/a-new-variant-of-mutational-and-polymorphic-signatures-in-the-erg11-ge-peer-reviewed-fulltext-article-IDR |
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