Resistance to the “last resort” antibiotic colistin: a single-zinc mechanism for phosphointermediate formation in MCR enzymes

Emily Lythell; Reynier Suardíaz; Philip Hinchliffe; Chonnikan Hanpaibool; Surawit Visitsatthawong; A. Sofia F. Oliveira; Eric J. M. Lang; Panida Surawatanawong; Vannajan Sanghiran Lee; Thanyada Rungrotmongkol; Natalie Fey; James Spencer; Adrian J. Mulholland

doi:10.1039/D0CC02520H

Resistance to the “last resort” antibiotic colistin: a single-zinc mechanism for phosphointermediate formation in MCR enzymes†

Emily Lythell,

‡^ab Reynier Suardíaz,

‡^acde Philip Hinchliffe,

‡^b Chonnikan Hanpaibool,^f Surawit Visitsatthawong,^g A. Sofia F. Oliveira,^ac Eric J. M. Lang,

^a Panida Surawatanawong,

^g Vannajan Sanghiran Lee,^h Thanyada Rungrotmongkol,

^fi Natalie Fey,

^a James Spencer

*^b and Adrian J. Mulholland

*^a

Author affiliations

* Corresponding authors

^a Centre for Computational Chemistry, School of Chemistry, University of Bristol, Cantock's Close, Bristol, UK
E-mail: Adrian.Mulholland@bristol.ac.uk

^b School of Cellular and Molecular Medicine, University of Bristol, University Walk, Bristol, UK
E-mail: Jim.Spencer@bristol.ac.uk

^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.

Chemical Communications

Resistance to the “last resort” antibiotic colistin: a single-zinc mechanism for phosphointermediate formation in MCR enzymes†

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Resistance to the “last resort” antibiotic colistin: a single-zinc mechanism for phosphointermediate formation in MCR enzymes

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