Computational Analysis of the Molecular Mechanism of RamR Mutations Contributing to Antimicrobial Resistance in Salmonella enterica. Issue 1 (December 2017)

• Record Type: Journal Article
• Authors: Liu, Yen-Yi; Chen, Chih-Chieh
• Is Part Of: Scientific reports. Volume 7:Issue 1(2017)
• Page Start: 1
• Page End: 9
• Publication Date: 2017-12
• Subjects: Natural history -- Research -- Periodicals; Biology -- Research -- Periodicals; Physical sciences -- Research -- Periodicals; Earth sciences -- Research -- Periodicals; Environmental sciences -- Research -- Periodicals; 502.85
• DOI: 10.1038/s41598-017-14008-5
• Languages: English
• ISSNs: 2045-2322

Abstract

Abstract 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. InSalmonella enterica, the RND pump is translated from theacrAB gene, which is regulated by the activator RamA. Many MEP-caused AMR strains have highramA 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 theramA 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 theramA promoter. The present results suggest that the three mutations alter the RamR structure, resulting in decreased DNA-binding affinity.