Molecular insights into functional differences between mcr-3- and mcr-1-mediated colistin resistance

Li, Hui, Yang, Lu, Liu, Zhihai, Yin, Wenjuan, Liu, Dejun, Shen, Yingbo, Walsh, Timothy ORCID: https://orcid.org/0000-0003-4315-4096, Shao, Bing and Wang, Yang 2018. Molecular insights into functional differences between mcr-3- and mcr-1-mediated colistin resistance. Antimicrobial Agents and Chemotherapy , AAC.00366. 10.1128/AAC.00366-18

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Abstract

The global emergence of plasmid-mediated colistin resistance genes mcr-1 and mcr-3 has threatened the role of the “last resort” drug colistin in the defense against infections caused by multidrug-resistant Gram-negative bacteria. However, functional differences between these two genes in mediating colistin resistance remains poorly understood. Protein sequence alignment of MCR-3 and MCR-1 was therefore conducted in Clustal Omega to identify sequence divergence. The molecular recognition of lipid A head group phosphatidylethanolamine and MCR-3 enzyme was studied by homology modeling and molecular docking, with the catalytic mechanism of MCR-3 also being explored. Thr277 in MCR-3 was validated as the key amino acid residue responsible for the catalytic reaction using site-directed mutagenesis and was shown to act as a nucleophile. Lipid A modification induced by the MCR-3 and MCR-1 enzymes was confirmed by electrospray ionization time-of-flight mass spectrometry. Far-UV circular dichroism spectra of the MCR-3 and MCR-1 enzymes suggested that MCR-3 was more thermostable than MCR-1, with a melting temperature of 66.19°C compared with 61.14°C for MCR-1. These data provided molecular insight into the functional differences between mcr-3 and mcr-1 in conferring colistin resistance.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Publisher:	American Society for Microbiology
ISSN:	0066-4804
Date of First Compliant Deposit:	9 August 2018
Date of Acceptance:	8 June 2018
Last Modified:	09 Nov 2023 19:52
URI:	https://orca.cardiff.ac.uk/id/eprint/114057

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