{"title":"由于 CDR1 表达增加,白色念珠菌中的 TAC1b 突变会降低对 manogepix 的敏感性。","authors":"Tatsuro Hirayama, Taiga Miyazaki, Rina Tanaka, Natsume Kitahori, Masataka Yoshida, Kazuaki Takeda, Shotaro Ide, Naoki Iwanaga, Masato Tashiro, Takahiro Takazono, Koichi Izumikawa, Katsunori Yanagihara, Koichi Makimura, Kazuhiro Tsukamoto, Hiroshi Mukae","doi":"10.1128/aac.01508-24","DOIUrl":null,"url":null,"abstract":"<p><p><i>Candida auris</i> is an emerging pathogenic fungus that is highly resistant to existing antifungal drugs. Manogepix is a novel antifungal agent that exerts antifungal activity by inhibiting glycosylphosphatidylinositol anchor biosynthesis. Although the mechanisms of resistance of <i>Candida</i> species to manogepix have been reported previously, those of <i>C. auris</i> are yet to be studied. To investigate the resistance mechanisms of <i>C. auris</i>, we exposed a clinical isolate (clade I) to manogepix <i>in vitro</i> and generated strains with reduced susceptibility to manogepix. A search for gain-of-function mutations that upregulate efflux pump expression confirmed the presence of the D865N amino acid mutation in <i>TAC1b</i>. We used the clustered regularly interspaced short palindromic repeats-Cas9 system to create a recovery strain (N865D) in which only this single nucleotide mutation was returned to the wild-type sequence. We generated a mutant strain by introducing only the D865N mutation into the parent strain and a different clade strain (clade III). The D865N mutant strains were clearly less susceptible to manogepix than the parental strains and exhibited high <i>CDR1</i> expression. Moreover, we generated a strain deficient in <i>CDR1</i> and confirmed that this strain had significantly increased susceptibility to manogepix. Thus, the present study demonstrated that the <i>TAC1b</i> mutation in <i>C. auris</i> upregulates <i>CDR1</i> expression and decreases its susceptibility to manogepix.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0150824"},"PeriodicalIF":4.1000,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"<i>TAC1b</i> mutation in <i>Candida auris</i> decreases manogepix susceptibility owing to increased <i>CDR1</i> expression.\",\"authors\":\"Tatsuro Hirayama, Taiga Miyazaki, Rina Tanaka, Natsume Kitahori, Masataka Yoshida, Kazuaki Takeda, Shotaro Ide, Naoki Iwanaga, Masato Tashiro, Takahiro Takazono, Koichi Izumikawa, Katsunori Yanagihara, Koichi Makimura, Kazuhiro Tsukamoto, Hiroshi Mukae\",\"doi\":\"10.1128/aac.01508-24\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p><i>Candida auris</i> is an emerging pathogenic fungus that is highly resistant to existing antifungal drugs. Manogepix is a novel antifungal agent that exerts antifungal activity by inhibiting glycosylphosphatidylinositol anchor biosynthesis. Although the mechanisms of resistance of <i>Candida</i> species to manogepix have been reported previously, those of <i>C. auris</i> are yet to be studied. To investigate the resistance mechanisms of <i>C. auris</i>, we exposed a clinical isolate (clade I) to manogepix <i>in vitro</i> and generated strains with reduced susceptibility to manogepix. A search for gain-of-function mutations that upregulate efflux pump expression confirmed the presence of the D865N amino acid mutation in <i>TAC1b</i>. We used the clustered regularly interspaced short palindromic repeats-Cas9 system to create a recovery strain (N865D) in which only this single nucleotide mutation was returned to the wild-type sequence. We generated a mutant strain by introducing only the D865N mutation into the parent strain and a different clade strain (clade III). The D865N mutant strains were clearly less susceptible to manogepix than the parental strains and exhibited high <i>CDR1</i> expression. Moreover, we generated a strain deficient in <i>CDR1</i> and confirmed that this strain had significantly increased susceptibility to manogepix. Thus, the present study demonstrated that the <i>TAC1b</i> mutation in <i>C. auris</i> upregulates <i>CDR1</i> expression and decreases its susceptibility to manogepix.</p>\",\"PeriodicalId\":8152,\"journal\":{\"name\":\"Antimicrobial Agents and Chemotherapy\",\"volume\":\" \",\"pages\":\"e0150824\"},\"PeriodicalIF\":4.1000,\"publicationDate\":\"2024-12-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Antimicrobial Agents and Chemotherapy\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1128/aac.01508-24\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"MICROBIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Antimicrobial Agents and Chemotherapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1128/aac.01508-24","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"MICROBIOLOGY","Score":null,"Total":0}
TAC1b mutation in Candida auris decreases manogepix susceptibility owing to increased CDR1 expression.
Candida auris is an emerging pathogenic fungus that is highly resistant to existing antifungal drugs. Manogepix is a novel antifungal agent that exerts antifungal activity by inhibiting glycosylphosphatidylinositol anchor biosynthesis. Although the mechanisms of resistance of Candida species to manogepix have been reported previously, those of C. auris are yet to be studied. To investigate the resistance mechanisms of C. auris, we exposed a clinical isolate (clade I) to manogepix in vitro and generated strains with reduced susceptibility to manogepix. A search for gain-of-function mutations that upregulate efflux pump expression confirmed the presence of the D865N amino acid mutation in TAC1b. We used the clustered regularly interspaced short palindromic repeats-Cas9 system to create a recovery strain (N865D) in which only this single nucleotide mutation was returned to the wild-type sequence. We generated a mutant strain by introducing only the D865N mutation into the parent strain and a different clade strain (clade III). The D865N mutant strains were clearly less susceptible to manogepix than the parental strains and exhibited high CDR1 expression. Moreover, we generated a strain deficient in CDR1 and confirmed that this strain had significantly increased susceptibility to manogepix. Thus, the present study demonstrated that the TAC1b mutation in C. auris upregulates CDR1 expression and decreases its susceptibility to manogepix.
期刊介绍:
Antimicrobial Agents and Chemotherapy (AAC) features interdisciplinary studies that build our understanding of the underlying mechanisms and therapeutic applications of antimicrobial and antiparasitic agents and chemotherapy.