Phenotypic and genotypic characterization of daptomycin-resistant methicillin-resistant Staphylococcus aureus strains: relative roles of mprF and dlt operons.
Development of in vivo daptomycin resistance (DAP-R) among Staphylococcus aureus clinical isolates, in association with clinical treatment failures, has become a major therapeutic problem. This issue is especially relevant to methicillin-resistant S. aureus (MRSA) strains in the context of invasive...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4166420?pdf=render |
| _version_ | 1818772879185018880 |
|---|---|
| author | Nagendra N Mishra Arnold S Bayer Christopher Weidenmaier Timo Grau Stefanie Wanner Stefania Stefani Viviana Cafiso Taschia Bertuccio Michael R Yeaman Cynthia C Nast Soo-Jin Yang |
| author_facet | Nagendra N Mishra Arnold S Bayer Christopher Weidenmaier Timo Grau Stefanie Wanner Stefania Stefani Viviana Cafiso Taschia Bertuccio Michael R Yeaman Cynthia C Nast Soo-Jin Yang |
| author_sort | Nagendra N Mishra |
| collection | DOAJ |
| description | Development of in vivo daptomycin resistance (DAP-R) among Staphylococcus aureus clinical isolates, in association with clinical treatment failures, has become a major therapeutic problem. This issue is especially relevant to methicillin-resistant S. aureus (MRSA) strains in the context of invasive endovascular infections. In the current study, we used three well-characterized and clinically-derived DAP-susceptible (DAP-S) vs. resistant (DAP-R) MRSA strain-pairs to elucidate potential genotypic mechanisms of the DAP-R phenotype. In comparison to the DAP-S parental strains, DAP-R isolates demonstrated (i) altered expression of two key determinants of net positive surface charge, either during exponential or stationary growth phases (i.e., dysregulation of dltA and mprF), (ii) a significant increase in the D-alanylated wall teichoic acid (WTA) content in DAP-R strains, reflecting DltA gain-in-function; (iii) heightened elaboration of lysinylated-phosphatidylglyderol (L-PG) in DAP-R strains, reflecting MprF gain-in-function; (iv) increased cell membrane (CM) fluidity, and (v) significantly reduced susceptibility to prototypic cationic host defense peptides of platelet and leukocyte origins. In the tested DAP-R strains, genes conferring positive surface charge were dysregulated, and their functionality altered. However, there were no correlations between relative surface positive charge or cell wall thickness and the observed DAP-R phenotype. Thus, charge repulsion mechanisms via altered surface charge may not be sufficient to explain the DAP-R outcome. Instead, changes in the compositional or biophysical order of the DAP CM target of such DAP-R strains (i.e., increased fluidity) may be essential to this phenotype. Taken together, DAP-R in S. aureus appears to involve multi-factorial and strain-specific adaptive mechanisms. |
| first_indexed | 2024-12-18T10:16:22Z |
| format | Article |
| id | doaj.art-ce533c70c5fe476cb1e4d180dcca77f3 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-18T10:16:22Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-ce533c70c5fe476cb1e4d180dcca77f32022-12-21T21:11:17ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0199e10742610.1371/journal.pone.0107426Phenotypic and genotypic characterization of daptomycin-resistant methicillin-resistant Staphylococcus aureus strains: relative roles of mprF and dlt operons.Nagendra N MishraArnold S BayerChristopher WeidenmaierTimo GrauStefanie WannerStefania StefaniViviana CafisoTaschia BertuccioMichael R YeamanCynthia C NastSoo-Jin YangDevelopment of in vivo daptomycin resistance (DAP-R) among Staphylococcus aureus clinical isolates, in association with clinical treatment failures, has become a major therapeutic problem. This issue is especially relevant to methicillin-resistant S. aureus (MRSA) strains in the context of invasive endovascular infections. In the current study, we used three well-characterized and clinically-derived DAP-susceptible (DAP-S) vs. resistant (DAP-R) MRSA strain-pairs to elucidate potential genotypic mechanisms of the DAP-R phenotype. In comparison to the DAP-S parental strains, DAP-R isolates demonstrated (i) altered expression of two key determinants of net positive surface charge, either during exponential or stationary growth phases (i.e., dysregulation of dltA and mprF), (ii) a significant increase in the D-alanylated wall teichoic acid (WTA) content in DAP-R strains, reflecting DltA gain-in-function; (iii) heightened elaboration of lysinylated-phosphatidylglyderol (L-PG) in DAP-R strains, reflecting MprF gain-in-function; (iv) increased cell membrane (CM) fluidity, and (v) significantly reduced susceptibility to prototypic cationic host defense peptides of platelet and leukocyte origins. In the tested DAP-R strains, genes conferring positive surface charge were dysregulated, and their functionality altered. However, there were no correlations between relative surface positive charge or cell wall thickness and the observed DAP-R phenotype. Thus, charge repulsion mechanisms via altered surface charge may not be sufficient to explain the DAP-R outcome. Instead, changes in the compositional or biophysical order of the DAP CM target of such DAP-R strains (i.e., increased fluidity) may be essential to this phenotype. Taken together, DAP-R in S. aureus appears to involve multi-factorial and strain-specific adaptive mechanisms.http://europepmc.org/articles/PMC4166420?pdf=render |
| spellingShingle | Nagendra N Mishra Arnold S Bayer Christopher Weidenmaier Timo Grau Stefanie Wanner Stefania Stefani Viviana Cafiso Taschia Bertuccio Michael R Yeaman Cynthia C Nast Soo-Jin Yang Phenotypic and genotypic characterization of daptomycin-resistant methicillin-resistant Staphylococcus aureus strains: relative roles of mprF and dlt operons. PLoS ONE |
| title | Phenotypic and genotypic characterization of daptomycin-resistant methicillin-resistant Staphylococcus aureus strains: relative roles of mprF and dlt operons. |
| title_full | Phenotypic and genotypic characterization of daptomycin-resistant methicillin-resistant Staphylococcus aureus strains: relative roles of mprF and dlt operons. |
| title_fullStr | Phenotypic and genotypic characterization of daptomycin-resistant methicillin-resistant Staphylococcus aureus strains: relative roles of mprF and dlt operons. |
| title_full_unstemmed | Phenotypic and genotypic characterization of daptomycin-resistant methicillin-resistant Staphylococcus aureus strains: relative roles of mprF and dlt operons. |
| title_short | Phenotypic and genotypic characterization of daptomycin-resistant methicillin-resistant Staphylococcus aureus strains: relative roles of mprF and dlt operons. |
| title_sort | phenotypic and genotypic characterization of daptomycin resistant methicillin resistant staphylococcus aureus strains relative roles of mprf and dlt operons |
| url | http://europepmc.org/articles/PMC4166420?pdf=render |
| work_keys_str_mv | AT nagendranmishra phenotypicandgenotypiccharacterizationofdaptomycinresistantmethicillinresistantstaphylococcusaureusstrainsrelativerolesofmprfanddltoperons AT arnoldsbayer phenotypicandgenotypiccharacterizationofdaptomycinresistantmethicillinresistantstaphylococcusaureusstrainsrelativerolesofmprfanddltoperons AT christopherweidenmaier phenotypicandgenotypiccharacterizationofdaptomycinresistantmethicillinresistantstaphylococcusaureusstrainsrelativerolesofmprfanddltoperons AT timograu phenotypicandgenotypiccharacterizationofdaptomycinresistantmethicillinresistantstaphylococcusaureusstrainsrelativerolesofmprfanddltoperons AT stefaniewanner phenotypicandgenotypiccharacterizationofdaptomycinresistantmethicillinresistantstaphylococcusaureusstrainsrelativerolesofmprfanddltoperons AT stefaniastefani phenotypicandgenotypiccharacterizationofdaptomycinresistantmethicillinresistantstaphylococcusaureusstrainsrelativerolesofmprfanddltoperons AT vivianacafiso phenotypicandgenotypiccharacterizationofdaptomycinresistantmethicillinresistantstaphylococcusaureusstrainsrelativerolesofmprfanddltoperons AT taschiabertuccio phenotypicandgenotypiccharacterizationofdaptomycinresistantmethicillinresistantstaphylococcusaureusstrainsrelativerolesofmprfanddltoperons AT michaelryeaman phenotypicandgenotypiccharacterizationofdaptomycinresistantmethicillinresistantstaphylococcusaureusstrainsrelativerolesofmprfanddltoperons AT cynthiacnast phenotypicandgenotypiccharacterizationofdaptomycinresistantmethicillinresistantstaphylococcusaureusstrainsrelativerolesofmprfanddltoperons AT soojinyang phenotypicandgenotypiccharacterizationofdaptomycinresistantmethicillinresistantstaphylococcusaureusstrainsrelativerolesofmprfanddltoperons |