Cargando…
Computational Analysis of the Molecular Mechanism of RamR Mutations Contributing to Antimicrobial Resistance in Salmonella enterica
Antimicrobial resistance (AMR) in pathogenic microorganisms with multidrug resistance (MDR) constitutes a severe threat to human health. A major causative mechanism of AMR is mediated through the multidrug efflux pump (MEP). The resistance-nodulation-division superfamily (RND family) of Gram-negativ...
Autores principales: | , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5645378/ https://www.ncbi.nlm.nih.gov/pubmed/29042652 http://dx.doi.org/10.1038/s41598-017-14008-5 |
_version_ | 1783271876563304448 |
---|---|
author | Liu, Yen-Yi Chen, Chih-Chieh |
author_facet | Liu, Yen-Yi Chen, Chih-Chieh |
author_sort | Liu, Yen-Yi |
collection | PubMed |
description | Antimicrobial resistance (AMR) in pathogenic microorganisms with multidrug resistance (MDR) constitutes a severe threat to human health. A major causative mechanism of AMR is mediated through the multidrug efflux pump (MEP). The resistance-nodulation-division superfamily (RND family) of Gram-negative bacteria is usually the major cause of MDR in clinical studies. In Salmonella enterica, the RND pump is translated from the acrAB gene, which is regulated by the activator RamA. Many MEP-caused AMR strains have high ramA gene expression due to mutations in RamR, which has a homodimeric structure comprising the dimerization domain and DNA-binding domain (DBD). Three mutations on the dimerization domain, namely Y59H, M84I, and E160D, are far from the DBD; the molecular mechanism through which they influence RamR’s binding affinity to the ramA gene promoter and consequently disrupt RamA remains unclear. The present study conducted molecular dynamics simulations, binding free energy calculations, and normal mode analysis to investigate the mechanism through which Y59H, M84I, and E160D mutations on the dimerization domain influence the binding affinity of RamR to the ramA promoter. The present results suggest that the three mutations alter the RamR structure, resulting in decreased DNA-binding affinity. |
format | Online Article Text |
id | pubmed-5645378 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-56453782017-10-26 Computational Analysis of the Molecular Mechanism of RamR Mutations Contributing to Antimicrobial Resistance in Salmonella enterica Liu, Yen-Yi Chen, Chih-Chieh Sci Rep Article Antimicrobial resistance (AMR) in pathogenic microorganisms with multidrug resistance (MDR) constitutes a severe threat to human health. A major causative mechanism of AMR is mediated through the multidrug efflux pump (MEP). The resistance-nodulation-division superfamily (RND family) of Gram-negative bacteria is usually the major cause of MDR in clinical studies. In Salmonella enterica, the RND pump is translated from the acrAB gene, which is regulated by the activator RamA. Many MEP-caused AMR strains have high ramA gene expression due to mutations in RamR, which has a homodimeric structure comprising the dimerization domain and DNA-binding domain (DBD). Three mutations on the dimerization domain, namely Y59H, M84I, and E160D, are far from the DBD; the molecular mechanism through which they influence RamR’s binding affinity to the ramA gene promoter and consequently disrupt RamA remains unclear. The present study conducted molecular dynamics simulations, binding free energy calculations, and normal mode analysis to investigate the mechanism through which Y59H, M84I, and E160D mutations on the dimerization domain influence the binding affinity of RamR to the ramA promoter. The present results suggest that the three mutations alter the RamR structure, resulting in decreased DNA-binding affinity. Nature Publishing Group UK 2017-10-17 /pmc/articles/PMC5645378/ /pubmed/29042652 http://dx.doi.org/10.1038/s41598-017-14008-5 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Liu, Yen-Yi Chen, Chih-Chieh Computational Analysis of the Molecular Mechanism of RamR Mutations Contributing to Antimicrobial Resistance in Salmonella enterica |
title | Computational Analysis of the Molecular Mechanism of RamR Mutations Contributing to Antimicrobial Resistance in Salmonella enterica |
title_full | Computational Analysis of the Molecular Mechanism of RamR Mutations Contributing to Antimicrobial Resistance in Salmonella enterica |
title_fullStr | Computational Analysis of the Molecular Mechanism of RamR Mutations Contributing to Antimicrobial Resistance in Salmonella enterica |
title_full_unstemmed | Computational Analysis of the Molecular Mechanism of RamR Mutations Contributing to Antimicrobial Resistance in Salmonella enterica |
title_short | Computational Analysis of the Molecular Mechanism of RamR Mutations Contributing to Antimicrobial Resistance in Salmonella enterica |
title_sort | computational analysis of the molecular mechanism of ramr mutations contributing to antimicrobial resistance in salmonella enterica |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5645378/ https://www.ncbi.nlm.nih.gov/pubmed/29042652 http://dx.doi.org/10.1038/s41598-017-14008-5 |
work_keys_str_mv | AT liuyenyi computationalanalysisofthemolecularmechanismoframrmutationscontributingtoantimicrobialresistanceinsalmonellaenterica AT chenchihchieh computationalanalysisofthemolecularmechanismoframrmutationscontributingtoantimicrobialresistanceinsalmonellaenterica |