Resistance to the last resort antibiotic colistin: a single-zinc mechanism for phosphointermediate formation in MCR enzymes
* Corresponding authors
a Centre for Computational Chemistry, School of Chemistry, University of Bristol, Cantock's Close, Bristol, UK
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b School of Cellular and Molecular Medicine, University of Bristol, University Walk, Bristol, UK
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c School of Biochemistry, University of Bristol, University Walk, Bristol, UK
d Centre for Enzyme Innovation, School of Biological Sciences, Institute of Biological and Biomedical Sciences, University of Portsmouth, Portsmouth PO1 2DT, UK
e Department of Physical Chemistry, Faculty of Chemistry, Complutense University of Madrid, 28040 Madrid, Spain
f Structural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
g Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
h Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur 50603, Malaysia
i Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand
Abstract
MCR [mobile colistin resistance] enzymes catalyse phosphoethanolamine [PEA] addition to bacterial lipid A, threatening the last-resort antibiotic colistin. Molecular dynamics and density functional theory simulations indicate that monozinc MCR supports PEA transfer to the Thr285 acceptor, positioning MCR as a mono- rather than multinuclear member of the alkaline phosphatase superfamily.