Yeast Double Transporter Gene Deletion Library for Identification of Xenobiotic Carriers in Low or High Throughput

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dc.contributor.authorAlmeida, Ludimila Dias
dc.contributor.authorSilva, Ali Salim Faraj
dc.contributor.authorMota, Daniel Calixto
dc.contributor.authorVasconcelos, Adrielle Ayumi
dc.contributor.authorCamargo, Antonio Pedro
dc.contributor.authorPires, Gabriel Silva
dc.contributor.authorFurlan, Monique
dc.contributor.authorFreire, Helena Martins Ribeiro da Cunha
dc.contributor.authorKlippel, Angelica Hollunder [UNESP]
dc.contributor.authorSilva, Suelen Fernandes [UNESP]
dc.contributor.authorZanelli, Cleslei Fernando [UNESP]
dc.contributor.authorCarazzolle, Marcelo Falsarella
dc.contributor.authorOliver, Stephen G.
dc.contributor.authorBilsland, Elizabeth
dc.contributor.institutionUniversidade Estadual de Campinas (UNICAMP)
dc.contributor.institutionUniversidade Estadual Paulista (UNESP)
dc.contributor.institutionUniv Cambridge
dc.date.accessioned2022-04-28T17:21:11Z
dc.date.available2022-04-28T17:21:11Z
dc.date.issued2021-11-01
dc.description.abstractThe routes of uptake and efflux should be considered when developing new drugs so that they can effectively address their intracellular targets. As a general rule, drugs appear to enter cells via protein carriers that normally carry nutrients or metabolites. A previously developed pipeline that searched for drug transporters using Saccharomyces cerevisiae mutants carrying single-gene deletions identified import routes for most compounds tested. However, due to the redundancy of transporter functions, we propose that this methodology can be improved by utilizing double mutant strains in both low- and high-throughput screens. We constructed a library of over 14,000 strains harboring double deletions of genes encoding 122 nonessential plasma membrane transporters and performed low-and high-throughput screens identifying possible drug import routes for 23 compounds. In addition, the high-throughput assay enabled the identification of putative efflux routes for 21 compounds. Focusing on azole antifungals, we were able to identify the involvement of the myo-inositol transporter, Itr1p, in the uptake of these molecules and to confirm the role of Pdr5p in their export. IMPORTANCE Our library of double transporter deletion strains is a powerful tool for rapid identification of potential drug import and export routes, which can aid in determining the chemical groups necessary for transport via specific carriers. This information may be translated into a better design of drugs for optimal absorption by target tissues and the development of drugs whose utility is less likely to be compromised by the selection of resistant mutants.en
dc.description.affiliationUniv Campinas UNICAMP, Inst Biol, Dept Struct & Funct Biol, Synthet Biol Lab, Campinas, SP, Brazil
dc.description.affiliationUniv Campinas UNICAMP, Dept Genet Evolut Microbiol & Immunol, Inst Biol, Lab Genom & BioEnergy, Campinas, SP, Brazil
dc.description.affiliationSao Paulo State Univ UNESP, Sch Pharmaceut Sci, Araraquara, SP, Brazil
dc.description.affiliationSao Paulo State Univ UNESP, Chem Inst, Araraquara, SP, Brazil
dc.description.affiliationUniv Cambridge, Cambridge Syst Biol Ctr, Cambridge, England
dc.description.affiliationUniv Cambridge, Dept Biochem, Cambridge, England
dc.description.affiliationUnespSao Paulo State Univ UNESP, Sch Pharmaceut Sci, Araraquara, SP, Brazil
dc.description.affiliationUnespSao Paulo State Univ UNESP, Chem Inst, Araraquara, SP, Brazil
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description.sponsorshipBill and Melinda Gates Foundation
dc.description.sponsorshipUK Biotechnology and Biological Sciences Research Council
dc.description.sponsorshipCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.description.sponsorshipIdFAPESP: 2015/03553-6
dc.description.sponsorshipIdFAPESP: 2017/01986-8
dc.description.sponsorshipIdFAPESP: 2019/14146-3
dc.description.sponsorshipIdFAPESP: 2018/05328-8
dc.description.sponsorshipIdFAPESP: 2019/17876-2
dc.description.sponsorshipIdFAPESP: 2017/13015-7
dc.description.sponsorshipIdFAPESP: 2018/04240-0
dc.description.sponsorshipIdFAPESP: 2018/16672-1
dc.description.sponsorshipIdBill and Melinda Gates Foundation: OP1087646
dc.description.sponsorshipIdUK Biotechnology and Biological Sciences Research Council: BB/F008228/1
dc.description.sponsorshipIdCAPES: 001
dc.format.extent22
dc.identifier.citationMbio. Washington: Amer Soc Microbiology, v. 12, n. 6, 22 p., 2021.
dc.identifier.issn2150-7511
dc.identifier.urihttp://hdl.handle.net/11449/218458
dc.identifier.wosWOS:000736928500002
dc.language.isoeng
dc.publisherAmer Soc Microbiology
dc.relation.ispartofMbio
dc.sourceWeb of Science
dc.subjectnonessential transporter double-deletion library
dc.subjectplasma membrane transporter
dc.subjectdrug uptake
dc.subjectdrug efflux
dc.subjectxenobiotics
dc.subjectSaccharomyces cerevisiae
dc.subjectdrug transport
dc.subjectgenetic interactions
dc.subjectyeast
dc.titleYeast Double Transporter Gene Deletion Library for Identification of Xenobiotic Carriers in Low or High Throughputen
dc.typeArtigo
dcterms.rightsHolderAmer Soc Microbiology
unesp.author.orcid0000-0001-8145-4669[4]
unesp.author.orcid0000-0002-5354-1957[6]
unesp.author.orcid0000-0003-0684-3888[8]
unesp.author.orcid0000-0002-4376-6626[9]
unesp.author.orcid0000-0001-7831-1149[11]
unesp.author.orcid0000-0002-5474-2830[12]

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