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2021-02-15Zeitschriftenartikel DOI: 10.25646/9595
Genome-Wide Association Studies for the Detection of Genetic Variants Associated With Daptomycin and Ceftaroline Resistance in Staphylococcus aureus
dc.contributor.authorWeber, Robert E.
dc.contributor.authorFuchs, Stephan
dc.contributor.authorLayer, Franziska
dc.contributor.authorSommer, Anna
dc.contributor.authorBender, Jennifer K.
dc.contributor.authorThürmer, Andrea
dc.contributor.authorWerner, Guido
dc.contributor.authorStrommenger, Birgit
dc.date.accessioned2022-01-31T10:04:53Z
dc.date.available2022-01-31T10:04:53Z
dc.date.issued2021-02-15none
dc.identifier.other10.3389/fmicb.2021.639660
dc.identifier.other10.3389/fmicb.2021.639660
dc.identifier.urihttp://edoc.rki.de/176904/9290
dc.description.abstractBackground: As next generation sequencing (NGS) technologies have experienced a rapid development over the last decade, the investigation of the bacterial genetic architecture reveals a high potential to dissect causal loci of antibiotic resistance phenotypes. Although genome-wide association studies (GWAS) have been successfully applied for investigating the basis of resistance traits, complex resistance phenotypes have been omitted so far. For S. aureus this especially refers to antibiotics of last resort like daptomycin and ceftaroline. Therefore, we aimed to perform GWAS for the identification of genetic variants associated with DAP and CPT resistance in clinical S. aureus isolates. Materials/methods: To conduct microbial GWAS, we selected cases and controls according to their clonal background, date of isolation, and geographical origin. Association testing was performed with PLINK and SEER analysis. By using in silico analysis, we also searched for rare genetic variants in candidate loci that have previously been described to be involved in the development of corresponding resistance phenotypes. Results: GWAS revealed MprF P314L and L826F to be significantly associated with DAP resistance. These mutations were found to be homogenously distributed among clonal lineages suggesting convergent evolution. Additionally, rare and yet undescribed single nucleotide polymorphisms could be identified within mprF and putative candidate genes. Finally, we could show that each DAP resistant isolate exhibited at least one amino acid substitution within the open reading frame of mprF. Due to the presence of strong population stratification, no genetic variants could be associated with CPT resistance. However, the investigation of the staphylococcal cassette chromosome mec (SCCmec) revealed various mecA SNPs to be putatively linked with CPT resistance. Additionally, some CPT resistant isolates revealed no mecA mutations, supporting the hypothesis that further and still unknown resistance determinants are crucial for the development of CPT resistance in S. aureus. Conclusion: We hereby confirmed the potential of GWAS to identify genetic variants that are associated with antibiotic resistance traits in S. aureus. However, precautions need to be taken to prevent the detection of spurious associations. In addition, the implementation of different approaches is still essential to detect multiple forms of variations and mutations that occur with a low frequency.eng
dc.language.isoengnone
dc.publisherRobert Koch-Institut
dc.rights(CC BY 3.0 DE) Namensnennung 3.0 Deutschlandger
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/de/
dc.subjectGWASeng
dc.subjectdaptomycineng
dc.subjectceftarolineeng
dc.subjectS. aureuseng
dc.subjectantibiotic resistanceeng
dc.subjectPLINKeng
dc.subjectSEEReng
dc.subject.ddc610 Medizin und Gesundheitnone
dc.titleGenome-Wide Association Studies for the Detection of Genetic Variants Associated With Daptomycin and Ceftaroline Resistance in Staphylococcus aureusnone
dc.typearticle
dc.identifier.urnurn:nbn:de:0257-176904/9290-3
dc.identifier.doihttp://dx.doi.org/10.25646/9595
dc.type.versionpublishedVersionnone
local.edoc.container-titlefrontiers in Microbiologynone
local.edoc.type-nameZeitschriftenartikel
local.edoc.container-typeperiodical
local.edoc.container-type-nameZeitschrift
local.edoc.container-urlhttps://www.frontiersin.org/articles/10.3389/fmicb.2021.639660/full#h1none
local.edoc.container-publisher-namefrontiersnone
local.edoc.container-volume12none
local.edoc.container-year2021none
local.edoc.container-firstpage1none
local.edoc.container-lastpage15none
local.edoc.rki-departmentInfektionskrankheitennone
dc.description.versionPeer Reviewednone

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