Quantitative proteomics revealed the transition of ergosterol biosynthesis and drug transporters processes during the development of fungal fluconazole resistance

作者全名："Sui, Xinying; Cheng, Xinyu; Li, Zhaodi; Wang, Yonghong; Zhang, Zhenpeng; Yan, Ruyue; Chang, Lei; Li, Yanchang; Xu, Ping; Duan, Changzhu"

作者地址："[Sui, Xinying; Li, Zhaodi; Duan, Changzhu] Chongqing Med Univ, Mol Med & Canc Res Ctr, Dept Cell Biol & Genet, Chongqing 400016, Peoples R China; [Sui, Xinying; Li, Zhaodi; Zhang, Zhenpeng; Yan, Ruyue; Chang, Lei; Li, Yanchang; Xu, Ping] Chinese Acad Med Sci, Res Unit Proteom & Res & Dev New Drug, Natl Ctr Prot Sci Beijing, Beijing Proteome Res Ctr,State Key Lab Proteom,Ins, Beijing 102206, Peoples R China; [Cheng, Xinyu; Li, Yanchang; Xu, Ping] Anhui Med Univ, Sch Basic Med, Hefei 230032, Anhui, Peoples R China; [Wang, Yonghong; Xu, Ping] Guizhou Univ, Sch Med, Dept Biomed, Guiyang 550025, Peoples R China; [Yan, Ruyue; Xu, Ping] China Med Univ, Sch Publ Hlth, Dept Toxicol, Shenyang 110122, Peoples R China"

通信作者："Duan, CZ (通讯作者)，Chongqing Med Univ, Mol Med & Canc Res Ctr, Dept Cell Biol & Genet, Chongqing 400016, Peoples R China.; Li, YC; Xu, P (通讯作者)，Chinese Acad Med Sci, Res Unit Proteom & Res & Dev New Drug, Natl Ctr Prot Sci Beijing, Beijing Proteome Res Ctr,State Key Lab Proteom,Ins, Beijing 102206, Peoples R China."

来源：BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001057798100001

JCR分区：Q3

影响因子：2.6

年份：2023

卷号：1866

期号：3

开始页：　

结束页：　

文献类型：Article

关键词：Fungal resistance; Fluconazole; Ergosterol; ABC transporter; Ubiquitination; Proteomics

摘要："Fungal infections and antifungal resistance are the increasing global public health concerns. Mechanisms of fungal resistance include alterations in drug-target interactions, detoxification by high expression of drug efflux transporters, and permeability barriers associated with biofilms. However, the systematic panorama and dynamic changes of the relevant biological processes of fungal drug resistance acquisition remain limited. In this study, we developed a yeast model of resistance to prolonged fluconazole treatment and utilized the isobaric labels TMT (tandem mass tag)-based quantitative proteomics to analyze the proteome composition and changes in native, short-time fluconazole stimulated and drug-resistant strains. The proteome exhibited significant dynamic range at the beginning of treatment but returned to normal condition upon acquisition drug resistance. The sterol pathway responded strongly under a short time of fluconazole treatment, with increased transcript levels of most enzymes facilitating greater protein expression. With the drug resistance acquisition, the sterol pathway returned to normal state, while the expression of efflux pump proteins increased obviously on the transcription level. Finally, multiple efflux pump proteins showed high expression in drug-resistant strain. Thus, families of sterol pathway and efflux pump proteins, which are closely associated with drug resistance mechanisms, may play different roles at different nodes in the process of drug resistance acquisition. Our findings uncover the relatively important role of efflux pump proteins in the acquisition of fluconazole resistance and highlight its potential as the vital antifungal targets."

基金机构："Chinese National Basic Research Programs [2017YFA0505002, 32071431]; National Natural Science Foundation of China [32070668, 31901037, AWS17J008]; Innovation Foundation of Medicine [20SWAQX34, 2019-I2M-5-017, SKLP-Y201901]; CAMS Innovation Fund for Medical Sciences [SKLP-K201704]; Foundation of State Key Lab of Proteomics [J200001, AMMS-QNTB-2022-003]; Beijing-Tianjin-Hebei Basic Research Cooperation Project; [2020YFE0202200]; [19SWAQ17]; [SKLP-O201905]"

基金资助正文："This study was supported by the Chinese National Basic Research Programs (2020YFE0202200 and 2017YFA0505002) , the National Natural Science Foundation of China (32071431, 32070668 and 31901037) , the Innovation Foundation of Medicine (AMMS-QNTB-2022-003, AWS17J008, 19SWAQ17, 20SWAQX34) , the CAMS Innovation Fund for Medical Sciences (2019-I2M-5-017) , the Foundation of State Key Lab of Proteomics (SKLP-Y201901, SKLP-K201704, SKLP-O201905) , and the Beijing-Tianjin-Hebei Basic Research Cooperation Project (J200001) ."