Prayagraj Fandilolu, Chandan Kumar, Dushyant Palia, Susan Idicula-Thomas
{"title":"研究 ERG11 的正选基因和突变位点在白色念珠菌耐药性中的作用","authors":"Prayagraj Fandilolu, Chandan Kumar, Dushyant Palia, Susan Idicula-Thomas","doi":"10.1007/s00203-024-04159-1","DOIUrl":null,"url":null,"abstract":"<div><p>The steep increase in acquired drug resistance in <i>Candida</i> isolates has posed a great challenge in the clinical management of candidiasis globally. Information of genes and codon sites that are positively selected during evolution can provide insights into the mechanisms driving antifungal resistance in <i>Candida</i>. This study aimed to create a manually curated list of genes of <i>Candida</i> spp<i>.</i> reported to be associated with antifungal resistance in literature, and further investigate the structure-function implications of positively selected genes and mutation sites. Sequence analysis of antifungal drug resistance associated gene sequences from various species and strains of <i>Candida</i> revealed that <i>ERG11</i> and <i>MRR1</i> of <i>C. albicans</i> were positively selected during evolution. Four sites in <i>ERG11</i> and two sites in <i>MRR1</i> of <i>C. albicans</i> were positively selected and associated with drug resistance. These four sites (132, 405, 450, and 464) of <i>ERG11</i> are predictive markers for azole resistance and have evolved over time. A well-characterized crystal structure of sterol-14-α-demethylase (CYP51) encoded by <i>ERG11</i> is available in PDB. Therefore, the stability of CYP51 in complex with fluconazole was evaluated using MD simulations and molecular docking studies for two mutations (Y132F and Y132H) reported to be associated with azole resistance in literature. These mutations induced high flexibility in functional motifs of CYP51. It was also observed that residues such as I304, G308, and I379 of CYP51 play a critical role in fluconazole binding affinity. The insights gained from this study can further guide drug design strategies addressing antimicrobial resistance.</p></div>","PeriodicalId":8279,"journal":{"name":"Archives of Microbiology","volume":"206 11","pages":""},"PeriodicalIF":2.3000,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Investigating role of positively selected genes and mutation sites of ERG11 in drug resistance of Candida albicans\",\"authors\":\"Prayagraj Fandilolu, Chandan Kumar, Dushyant Palia, Susan Idicula-Thomas\",\"doi\":\"10.1007/s00203-024-04159-1\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>The steep increase in acquired drug resistance in <i>Candida</i> isolates has posed a great challenge in the clinical management of candidiasis globally. Information of genes and codon sites that are positively selected during evolution can provide insights into the mechanisms driving antifungal resistance in <i>Candida</i>. This study aimed to create a manually curated list of genes of <i>Candida</i> spp<i>.</i> reported to be associated with antifungal resistance in literature, and further investigate the structure-function implications of positively selected genes and mutation sites. Sequence analysis of antifungal drug resistance associated gene sequences from various species and strains of <i>Candida</i> revealed that <i>ERG11</i> and <i>MRR1</i> of <i>C. albicans</i> were positively selected during evolution. Four sites in <i>ERG11</i> and two sites in <i>MRR1</i> of <i>C. albicans</i> were positively selected and associated with drug resistance. These four sites (132, 405, 450, and 464) of <i>ERG11</i> are predictive markers for azole resistance and have evolved over time. A well-characterized crystal structure of sterol-14-α-demethylase (CYP51) encoded by <i>ERG11</i> is available in PDB. Therefore, the stability of CYP51 in complex with fluconazole was evaluated using MD simulations and molecular docking studies for two mutations (Y132F and Y132H) reported to be associated with azole resistance in literature. These mutations induced high flexibility in functional motifs of CYP51. It was also observed that residues such as I304, G308, and I379 of CYP51 play a critical role in fluconazole binding affinity. The insights gained from this study can further guide drug design strategies addressing antimicrobial resistance.</p></div>\",\"PeriodicalId\":8279,\"journal\":{\"name\":\"Archives of Microbiology\",\"volume\":\"206 11\",\"pages\":\"\"},\"PeriodicalIF\":2.3000,\"publicationDate\":\"2024-10-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Archives of Microbiology\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://link.springer.com/article/10.1007/s00203-024-04159-1\",\"RegionNum\":3,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"MICROBIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Archives of Microbiology","FirstCategoryId":"99","ListUrlMain":"https://link.springer.com/article/10.1007/s00203-024-04159-1","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"MICROBIOLOGY","Score":null,"Total":0}
Investigating role of positively selected genes and mutation sites of ERG11 in drug resistance of Candida albicans
The steep increase in acquired drug resistance in Candida isolates has posed a great challenge in the clinical management of candidiasis globally. Information of genes and codon sites that are positively selected during evolution can provide insights into the mechanisms driving antifungal resistance in Candida. This study aimed to create a manually curated list of genes of Candida spp. reported to be associated with antifungal resistance in literature, and further investigate the structure-function implications of positively selected genes and mutation sites. Sequence analysis of antifungal drug resistance associated gene sequences from various species and strains of Candida revealed that ERG11 and MRR1 of C. albicans were positively selected during evolution. Four sites in ERG11 and two sites in MRR1 of C. albicans were positively selected and associated with drug resistance. These four sites (132, 405, 450, and 464) of ERG11 are predictive markers for azole resistance and have evolved over time. A well-characterized crystal structure of sterol-14-α-demethylase (CYP51) encoded by ERG11 is available in PDB. Therefore, the stability of CYP51 in complex with fluconazole was evaluated using MD simulations and molecular docking studies for two mutations (Y132F and Y132H) reported to be associated with azole resistance in literature. These mutations induced high flexibility in functional motifs of CYP51. It was also observed that residues such as I304, G308, and I379 of CYP51 play a critical role in fluconazole binding affinity. The insights gained from this study can further guide drug design strategies addressing antimicrobial resistance.
期刊介绍:
Research papers must make a significant and original contribution to
microbiology and be of interest to a broad readership. The results of any
experimental approach that meets these objectives are welcome, particularly
biochemical, molecular genetic, physiological, and/or physical investigations into
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acceptable in principle if new information, interpretations, or hypotheses
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