title: Membrane Insertion of a Dinuclear Polypyridylruthenium(II) Complex Revealed by Solid-State NMR and Molecular Dynamics Simulation: Implications for Selective Antibacterial Activity.
abstract: Dinuclear polypyridylruthenium(II) complexes bridged by a flexible methylene linker have received considerable interest as potential antibacterial agents. Their potency and uptake into bacterial cells is directly modulated by the length of the bridging linker, which has implicated membrane interactions as an essential feature of their mechanism of action. In this work, a combination of molecular dynamics (MD) simulations and solid-state NMR was used to present an atomistic model of a polypyridylruthenium(II) complex bound and incorporated into a bacterial membrane model. The results of31P,2H,1H, and13C NMR studies revealed that the antibacterial [{Ru(phen)2}2(μ-bb12)]4+complex (Rubb12), where phen = 1,10-phenanthroline and bb12= bis[4(4'-methyl-2,2'-bipyridyl)]-1,12-dodecane), incorporated into a negatively charged model bacterial membrane, but only associated with the surface of a charge-neutral model of a eukaryotic membrane. Furthermore, an inactive [{Ir(phen)2}2(μ-bb12)]6+(Irbb12) analogue, which is not taken up by bacterial cells, maintained only a surface-bound association with both bacterial and eukaryotic model membranes according to31P and2H NMR. The effects of Rubb12on31P chemical shift anisotropy and2H acyl chain order parameters for negatively charged membranes correlated with a membrane-spanning state of the complex according to MD simulation-in which the metal centers embed in the lipid head group region and the central void, created by the biconic shape of the complex, resulting in increasing disorder of lipid acyl chains and membrane-thinning. A transbilayer mechanism and membrane-spanning may be essential for the cellular uptake and antibacterial activity of this class of compounds.
authors: Computational Biophysics, IBM Research Australia , Melbourne, VIC 3010, Australia.|School of Chemistry, Bio21 Institute, University of Melbourne , Parkville, VIC 3010, Australia.
authors: Daniel K
authors: DK
authors: Weber
authors: School of Chemistry, Bio21 Institute, University of Melbourne , Parkville, VIC 3010, Australia.
authors: Marc-Antoine
authors: MA
authors: Sani
authors: Computational Biophysics, IBM Research Australia , Melbourne, VIC 3010, Australia.|School of Chemistry, Bio21 Institute, University of Melbourne , Parkville, VIC 3010, Australia.
authors: Matthew T
authors: MT
authors: Downton
authors: School of Chemistry, Bio21 Institute, University of Melbourne , Parkville, VIC 3010, Australia.
authors: Frances
authors: F
authors: Separovic
authors: School of Physical Sciences, University of Adelaide , Adelaide, SA 5005, Australia.|Centre for Biodiscovery & Molecular Development of Therapeutics, James Cook University , Townsville, QLD 4811, Australia.
authors: F Richard
authors: FR
authors: Keene
authors: School of Physical, Environmental and Mathematical Sciences, University of New South Wales, Australian Defence Force Academy , Canberra, ACT 2600, Australia.
authors: J Grant
authors: JG
authors: Collins
mesh_terms: D015082:2,2'-Dipyridyl / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008826:Microbial Sensitivity Tests; D056004:Molecular Dynamics Simulation; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012428:Ruthenium / Q000737:chemistry / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000166:cytology / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D011108:Polymers; D015082:2,2'-Dipyridyl; D012428:Ruthenium