Dynamic Behavior and Substrate Interactions of the Polymyxin Resistance Determinant MCR-1 Investigated by Extended Molecular Dynamics Simulations in the Membrane Environment

  1. Lythell, Emily 1
  2. Suardíaz, Reynier 12
  3. Hinchliffe, Philip 1
  4. Oliveira, Sofia 1
  5. van der Kamp, Marc 1
  6. Spencer, James 1
  7. Mulholland, Adrian 1
  1. 1 University of Bristol
    info

    University of Bristol

    Brístol, Reino Unido

    ROR https://ror.org/0524sp257

  2. 2 Universidad Complutense de Madrid
    info

    Universidad Complutense de Madrid

    Madrid, España

    ROR 02p0gd045

Revista:
ChemRxiv

Año de publicación: 2024

Tipo: Documento de Trabajo

DOI: 10.26434/CHEMRXIV-2024-81S4K GOOGLE SCHOLAR lock_openAcceso abierto editor

Resumen

The polymyxin colistin is an agent of last resort for treatment of severe infections by multiresistant Gram-negative opportunistic bacteria. Colistin resistance arises through covalent modification of lipid A disaccharide by phosphoethanolamine (PEtN) transferases, preventing colistin interaction. The Mobile Colistin Resistance (MCR) PEtN transferase is a plasmid-borne enzyme that is the major cause of colistin resistance in Escherichia coli, the most important antimicrobial resistant bacterial pathogen worldwide. Bacterial PEtN transferases like MCR comprise periplasmic catalytic and integral membrane domains, with mechanistic understanding largely based on studies of the former with limited information on the full-length enzyme. Previous investigations of a Neisseria meningitidis PEtN transferase identified that the catalytic domain can effectively dissociate from the transmembrane component and instead make extensive contacts with the membrane surface. Here we report extended molecular dynamics simulations of a model of full-length MCR-1, in a representative membrane comprising 80% of a PEtN donor substrate palmitoyloleoyl phosphoethanolamine (POPE) that explore the dynamic behavior of the enzyme and the impact upon it of zinc stoichiometry and of PEtN addition to the Thr285 acceptor residue. The results identify only limited movement of the two domains relative to one another, and that POPE can bind the likely “resting” state of the enzyme (mono-zinc with unmodified Thr285) in an orientation compatible with PEtN transfer to Thr285. Our data suggest domain motions in bacterial PEtN transferases to be condition-dependent and support a proposed “ping - pong” reaction mechanism with the mono-zinc enzyme competent to undertake the first stage.

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