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Reciprocal Regulation of Cephalosporin Resistance in Enterococcus faecalis
Antibiotic-resistant enterococci are major causes of hospital-acquired infections and therefore represent a serious public health problem. One well-known risk factor for the acquisition of hospital-acquired enterococcal infections is prior therapy with broad-spectrum cephalosporin antibiotics. Enter...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Microbiology
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3202758/ https://www.ncbi.nlm.nih.gov/pubmed/22045988 http://dx.doi.org/10.1128/mBio.00199-11 |
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author | Kristich, Christopher J. Little, Jaime L. Hall, Cherisse L. Hoff, Jessica S. |
author_facet | Kristich, Christopher J. Little, Jaime L. Hall, Cherisse L. Hoff, Jessica S. |
author_sort | Kristich, Christopher J. |
collection | PubMed |
description | Antibiotic-resistant enterococci are major causes of hospital-acquired infections and therefore represent a serious public health problem. One well-known risk factor for the acquisition of hospital-acquired enterococcal infections is prior therapy with broad-spectrum cephalosporin antibiotics. Enterococci can proliferate in patients undergoing cephalosporin therapy due to intrinsic cephalosporin resistance, a characteristic of the genus Enterococcus. However, the molecular basis for cephalosporin resistance in E. faecalis has yet to be adequately elucidated. Previously we determined that a putative Ser/Thr kinase, IreK (formerly PrkC), is required for intrinsic cephalosporin resistance in E. faecalis. Here we show that kinase activity is required for cephalosporin resistance and, further, that resistance in E. faecalis is reciprocally regulated by IreK and IreP, a PP2C-type protein phosphatase encoded immediately upstream of IreK. Mutants of two divergent lineages of E. faecalis lacking IreP exhibit remarkable hyperresistance to cephalosporins but not to antibiotics targeting other cellular processes. Further genetic analyses indicate that hyperresistance of the IreP mutant is mediated by the IreK kinase. Additionally, competition experiments reveal that hyperresistant ΔireP mutants exhibit a substantial fitness defect in the absence of antibiotics, providing an evolutionary rationale for the use of a complex signaling system to control intrinsic cephalosporin resistance. These results support a model in which IreK and IreP act antagonistically via protein phosphorylation and dephosphorylation as part of a signal transduction circuit to regulate cellular adaptation to cephalosporin-induced stress. |
format | Online Article Text |
id | pubmed-3202758 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | American Society of Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-32027582011-11-04 Reciprocal Regulation of Cephalosporin Resistance in Enterococcus faecalis Kristich, Christopher J. Little, Jaime L. Hall, Cherisse L. Hoff, Jessica S. mBio Research Article Antibiotic-resistant enterococci are major causes of hospital-acquired infections and therefore represent a serious public health problem. One well-known risk factor for the acquisition of hospital-acquired enterococcal infections is prior therapy with broad-spectrum cephalosporin antibiotics. Enterococci can proliferate in patients undergoing cephalosporin therapy due to intrinsic cephalosporin resistance, a characteristic of the genus Enterococcus. However, the molecular basis for cephalosporin resistance in E. faecalis has yet to be adequately elucidated. Previously we determined that a putative Ser/Thr kinase, IreK (formerly PrkC), is required for intrinsic cephalosporin resistance in E. faecalis. Here we show that kinase activity is required for cephalosporin resistance and, further, that resistance in E. faecalis is reciprocally regulated by IreK and IreP, a PP2C-type protein phosphatase encoded immediately upstream of IreK. Mutants of two divergent lineages of E. faecalis lacking IreP exhibit remarkable hyperresistance to cephalosporins but not to antibiotics targeting other cellular processes. Further genetic analyses indicate that hyperresistance of the IreP mutant is mediated by the IreK kinase. Additionally, competition experiments reveal that hyperresistant ΔireP mutants exhibit a substantial fitness defect in the absence of antibiotics, providing an evolutionary rationale for the use of a complex signaling system to control intrinsic cephalosporin resistance. These results support a model in which IreK and IreP act antagonistically via protein phosphorylation and dephosphorylation as part of a signal transduction circuit to regulate cellular adaptation to cephalosporin-induced stress. American Society of Microbiology 2011-11-01 /pmc/articles/PMC3202758/ /pubmed/22045988 http://dx.doi.org/10.1128/mBio.00199-11 Text en Copyright © 2011 Kristich et al. http://creativecommons.org/licenses/by-nc-sa/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported License (http://creativecommons.org/licenses/by-nc-sa/3.0/) , which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Kristich, Christopher J. Little, Jaime L. Hall, Cherisse L. Hoff, Jessica S. Reciprocal Regulation of Cephalosporin Resistance in Enterococcus faecalis |
title | Reciprocal Regulation of Cephalosporin Resistance in Enterococcus faecalis |
title_full | Reciprocal Regulation of Cephalosporin Resistance in Enterococcus faecalis |
title_fullStr | Reciprocal Regulation of Cephalosporin Resistance in Enterococcus faecalis |
title_full_unstemmed | Reciprocal Regulation of Cephalosporin Resistance in Enterococcus faecalis |
title_short | Reciprocal Regulation of Cephalosporin Resistance in Enterococcus faecalis |
title_sort | reciprocal regulation of cephalosporin resistance in enterococcus faecalis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3202758/ https://www.ncbi.nlm.nih.gov/pubmed/22045988 http://dx.doi.org/10.1128/mBio.00199-11 |
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