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

Lythell E 1 , Suardíaz R 2 , Hinchliffe P 3 , Hanpaibool C 4 , Visitsatthawong S 5 , Oliveira ASF 6 Show all authors , Lang EJM 7 , Surawatanawong P 5 , Lee VS 8 , Rungrotmongkol T 9 , Fey N 7 , Spencer J 3 , Mulholland AJ 7

Affiliations 

  • 1 Centre for Computational Chemistry, School of Chemistry, University of Bristol, Cantock's Close, Bristol, BS8 1TS, UK. Adrian.Mulholland@bristol.ac.uk and School of Cellular and Molecular Medicine, University of Bristol, University Walk, Bristol, BS8 1TD, UK. Jim.Spencer@bristol.ac.uk
  • 2 Centre for Computational Chemistry, School of Chemistry, University of Bristol, Cantock's Close, Bristol, BS8 1TS, UK. Adrian.Mulholland@bristol.ac.uk and School of Biochemistry, University of Bristol, University Walk, Bristol, BS8 1TD, UK and Centre for Enzyme Innovation, School of Biological Sciences, Institute of Biological and Biomedical Sciences, University of Portsmouth, Portsmouth PO1 2DT, UK and Department of Physical Chemistry, Faculty of Chemistry, Complutense University of Madrid, 28040 Madrid, Spain
  • 3 School of Cellular and Molecular Medicine, University of Bristol, University Walk, Bristol, BS8 1TD, UK. Jim.Spencer@bristol.ac.uk
  • 4 Structural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
  • 5 Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
  • 6 Centre for Computational Chemistry, School of Chemistry, University of Bristol, Cantock's Close, Bristol, BS8 1TS, UK. Adrian.Mulholland@bristol.ac.uk and School of Biochemistry, University of Bristol, University Walk, Bristol, BS8 1TD, UK
  • 7 Centre for Computational Chemistry, School of Chemistry, University of Bristol, Cantock's Close, Bristol, BS8 1TS, UK. Adrian.Mulholland@bristol.ac.uk
  • 8 Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur 50603, Malaysia
  • 9 Structural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand and Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand
Chem Commun (Camb), 2020 Jun 23;56(50):6874-6877.
PMID: 32432618 DOI: 10.1039/d0cc02520h

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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