Attenuating the emergence of anti-fungal drug resistance by harnessing synthetic lethal interactions in a model organism
dc.contributor.author | Usher, J | |
dc.contributor.author | Haynes, K | |
dc.date.accessioned | 2019-09-12T12:53:10Z | |
dc.date.issued | 2019-08-19 | |
dc.description.abstract | Drug resistance is a rapidly emerging concern, thus prompting the development of novel therapeutics or combinatorial therapy. Currently, combinatorial therapy targets are based on knowledge of drug mode of action and/or resistance mechanisms, constraining the number of target proteins. Unbiased genome-wide screens could reveal novel genetic components within interaction networks as potential targets in combination therapies. Testing this, in the context of antimicrobial resistance, we implemented an unbiased genome-wide screen, performed in Saccharomyces cerevisiae expressing a Candida glabrata PDR1+ gain-of-function allele. Gain-of-function mutations in this gene are the principal mediators of fluconazole resistance in this human fungal pathogen. Eighteen synthetically lethal S. cerevisiae genetic mutants were identified in cells expressing C. glabrata PDR1+. One mutant, lacking the histone acetyltransferase Gcn5, was investigated further. Deletion or drug-mediated inhibition of Gcn5 caused a lethal phenotype in C. glabrata cells expressing PDR1+ alleles. Moreover, deletion or drug-mediated inactivation of Gcn5, inhibited the emergence of fluconazole-resistant C. glabrata isolates in evolution experiments. Thus, taken together, the data generated in this study provides proof of concept that synthetically lethal genetic screens can identify novel candidate proteins that when therapeutically targeted could allow effective treatment of drug-resistant infections. | en_GB |
dc.identifier.citation | Vol. 15 (8), article e1008259 | en_GB |
dc.identifier.doi | 10.1371/journal.pgen.1008259 | |
dc.identifier.uri | http://hdl.handle.net/10871/38710 | |
dc.language.iso | en | en_GB |
dc.publisher | Public Library of Science | en_GB |
dc.relation.url | https://www.ncbi.nlm.nih.gov/pubmed/31425501 | en_GB |
dc.rights | © 2019 Usher, Haynes. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. | en_GB |
dc.title | Attenuating the emergence of anti-fungal drug resistance by harnessing synthetic lethal interactions in a model organism | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2019-09-12T12:53:10Z | |
exeter.place-of-publication | United States | en_GB |
dc.description | This is the final version. Available on open access from Public Library of Science via the DOI in this record | en_GB |
dc.description | Data Availability: All relevant data are within the manuscript and its Supporting Information files. | en_GB |
dc.identifier.eissn | 1553-7404 | |
dc.identifier.journal | PLoS Genetics | en_GB |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | en_GB |
dcterms.dateAccepted | 2019-06-20 | |
rioxxterms.version | VoR | en_GB |
rioxxterms.licenseref.startdate | 2019-08-19 | |
rioxxterms.type | Journal Article/Review | en_GB |
refterms.dateFCD | 2019-09-12T12:52:19Z | |
refterms.versionFCD | VoR | |
refterms.dateFOA | 2019-09-12T12:53:13Z | |
refterms.panel | A | en_GB |
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Except where otherwise noted, this item's licence is described as © 2019 Usher, Haynes. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.