Genome-Wide Association Studies for the Detection of Genetic Variants Associated With Daptomycin and Ceftaroline Resistance in Staphylococcus aureus
BackgroundAs 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...
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doaj-76b880df0361433aaa10a63ec68dbf012021-04-27T10:42:54ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2021-02-011210.3389/fmicb.2021.639660639660Genome-Wide Association Studies for the Detection of Genetic Variants Associated With Daptomycin and Ceftaroline Resistance in Staphylococcus aureusRobert E. Weber0Stephan Fuchs1Franziska Layer2Anna Sommer3Jennifer K. Bender4Andrea Thürmer5Guido Werner6Birgit Strommenger7Department of Infectious Diseases, Robert Koch-Institute, Wernigerode, GermanyMethodology and Research Infrastructure, Bioinformatics, Robert Koch-Institute, Berlin, GermanyDepartment of Infectious Diseases, Robert Koch-Institute, Wernigerode, GermanyDepartment of Infectious Diseases, Robert Koch-Institute, Wernigerode, GermanyDepartment of Infectious Diseases, Robert Koch-Institute, Wernigerode, GermanyMethodology and Research Infrastructure, Genome Sequencing, Robert Koch-Institute, Berlin, GermanyDepartment of Infectious Diseases, Robert Koch-Institute, Wernigerode, GermanyDepartment of Infectious Diseases, Robert Koch-Institute, Wernigerode, GermanyBackgroundAs 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/methodsTo 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.ResultsGWAS 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.ConclusionWe 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.https://www.frontiersin.org/articles/10.3389/fmicb.2021.639660/fullGWASdaptomycinceftarolineS. aureusantibiotic resistancePLINK |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Robert E. Weber Stephan Fuchs Franziska Layer Anna Sommer Jennifer K. Bender Andrea Thürmer Guido Werner Birgit Strommenger |
spellingShingle |
Robert E. Weber Stephan Fuchs Franziska Layer Anna Sommer Jennifer K. Bender Andrea Thürmer Guido Werner Birgit Strommenger Genome-Wide Association Studies for the Detection of Genetic Variants Associated With Daptomycin and Ceftaroline Resistance in Staphylococcus aureus Frontiers in Microbiology GWAS daptomycin ceftaroline S. aureus antibiotic resistance PLINK |
author_facet |
Robert E. Weber Stephan Fuchs Franziska Layer Anna Sommer Jennifer K. Bender Andrea Thürmer Guido Werner Birgit Strommenger |
author_sort |
Robert E. Weber |
title |
Genome-Wide Association Studies for the Detection of Genetic Variants Associated With Daptomycin and Ceftaroline Resistance in Staphylococcus aureus |
title_short |
Genome-Wide Association Studies for the Detection of Genetic Variants Associated With Daptomycin and Ceftaroline Resistance in Staphylococcus aureus |
title_full |
Genome-Wide Association Studies for the Detection of Genetic Variants Associated With Daptomycin and Ceftaroline Resistance in Staphylococcus aureus |
title_fullStr |
Genome-Wide Association Studies for the Detection of Genetic Variants Associated With Daptomycin and Ceftaroline Resistance in Staphylococcus aureus |
title_full_unstemmed |
Genome-Wide Association Studies for the Detection of Genetic Variants Associated With Daptomycin and Ceftaroline Resistance in Staphylococcus aureus |
title_sort |
genome-wide association studies for the detection of genetic variants associated with daptomycin and ceftaroline resistance in staphylococcus aureus |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Microbiology |
issn |
1664-302X |
publishDate |
2021-02-01 |
description |
BackgroundAs 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/methodsTo 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.ResultsGWAS 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.ConclusionWe 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. |
topic |
GWAS daptomycin ceftaroline S. aureus antibiotic resistance PLINK |
url |
https://www.frontiersin.org/articles/10.3389/fmicb.2021.639660/full |
work_keys_str_mv |
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