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Article: Native CRISPR-Cas-Mediated Genome Editing Enables Dissecting and Sensitizing Clinical Multidrug-Resistant P. aeruginosa

TitleNative CRISPR-Cas-Mediated Genome Editing Enables Dissecting and Sensitizing Clinical Multidrug-Resistant P. aeruginosa
Authors
Keywordsanti-resistance drug discovery
cationic peptidomimetics
collateral sensitivity
genome editing
multidrug efflux pump
Issue Date2019
PublisherElsevier (Cell Press): OAJ. The Journal's web site is located at http://cell.com/cell-reports
Citation
Cell Reports, 2019, v. 29 n. 6, p. 1707-1717.e3 How to Cite?
AbstractDespite being fundamentally important and having direct therapeutic implications, the functional genomics of the clinical isolates of multidrug-resistant (MDR) pathogens is often impeded by the lack of genome-editing tools. Here, we report the establishment of a highly efficient, in situ genome editing technique applicable in clinical and environmental isolates of the prototypic MDR pathogen P. aeruginosa by harnessing the endogenous type I-F CRISPR-Cas systems. Using this approach, we generate various reverse mutations in an epidemic MDR genotype, PA154197, and identify underlying resistance mechanisms that involve the extensive synergy among three different resistance determinants. Screening a series of ‘‘ancestor’’ mutant lines uncovers the remarkable sensitivity of the MDR line PA154197 to a class of small, cationic peptidomimetics, which sensitize PA154197 cells to antibiotics by perturbing outer-membrane permeability. These studies provide a framework for molecular genetics and anti-resistance drug discovery for clinically isolated MDR pathogens.
Persistent Identifierhttp://hdl.handle.net/10722/280269
ISSN
2019 Impact Factor: 8.109
2015 SCImago Journal Rankings: 8.588

 

DC FieldValueLanguage
dc.contributor.authorXu, Z-
dc.contributor.authorLi, M-
dc.contributor.authorLI, Y-
dc.contributor.authorCao, H-
dc.contributor.authorMiao, L-
dc.contributor.authorXu, Z-
dc.contributor.authorHiguchi, Y-
dc.contributor.authorYamasaki, S-
dc.contributor.authorNishino, K-
dc.contributor.authorWoo, PCY-
dc.contributor.authorXiang, H-
dc.contributor.authorYan, A-
dc.date.accessioned2020-01-21T11:50:59Z-
dc.date.available2020-01-21T11:50:59Z-
dc.date.issued2019-
dc.identifier.citationCell Reports, 2019, v. 29 n. 6, p. 1707-1717.e3-
dc.identifier.issn2211-1247-
dc.identifier.urihttp://hdl.handle.net/10722/280269-
dc.description.abstractDespite being fundamentally important and having direct therapeutic implications, the functional genomics of the clinical isolates of multidrug-resistant (MDR) pathogens is often impeded by the lack of genome-editing tools. Here, we report the establishment of a highly efficient, in situ genome editing technique applicable in clinical and environmental isolates of the prototypic MDR pathogen P. aeruginosa by harnessing the endogenous type I-F CRISPR-Cas systems. Using this approach, we generate various reverse mutations in an epidemic MDR genotype, PA154197, and identify underlying resistance mechanisms that involve the extensive synergy among three different resistance determinants. Screening a series of ‘‘ancestor’’ mutant lines uncovers the remarkable sensitivity of the MDR line PA154197 to a class of small, cationic peptidomimetics, which sensitize PA154197 cells to antibiotics by perturbing outer-membrane permeability. These studies provide a framework for molecular genetics and anti-resistance drug discovery for clinically isolated MDR pathogens.-
dc.languageeng-
dc.publisherElsevier (Cell Press): OAJ. The Journal's web site is located at http://cell.com/cell-reports-
dc.relation.ispartofCell Reports-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectanti-resistance drug discovery-
dc.subjectcationic peptidomimetics-
dc.subjectcollateral sensitivity-
dc.subjectgenome editing-
dc.subjectmultidrug efflux pump-
dc.titleNative CRISPR-Cas-Mediated Genome Editing Enables Dissecting and Sensitizing Clinical Multidrug-Resistant P. aeruginosa-
dc.typeArticle-
dc.identifier.emailXu, Z: zelingxu@connect.hku.hk-
dc.identifier.emailCao, H: hcao@hku.hk-
dc.identifier.emailWoo, PCY: pcywoo@hkucc.hku.hk-
dc.identifier.emailYan, A: ayan8@hku.hk-
dc.identifier.authorityWoo, PCY=rp00430-
dc.identifier.authorityYan, A=rp00823-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1016/j.celrep.2019.10.006-
dc.identifier.pmid31693906-
dc.identifier.scopuseid_2-s2.0-85074294750-
dc.identifier.hkuros308970-
dc.identifier.volume29-
dc.identifier.issue6-
dc.identifier.spage1707-
dc.identifier.epage1717.e3-
dc.publisher.placeUnited States-

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