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

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...

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Veröffentlicht in:	Chemical communications (Cambridge, England) England), 2020-06, Vol.56 (5), p.6874-6877
Hauptverfasser:	Lythell, Emily, Suardíaz, Reynier, Hinchliffe, Philip, Hanpaibool, Chonnikan, Visitsatthawong, Surawit, Oliveira, A. Sofia F, Lang, Eric J. M, Surawatanawong, Panida, Lee, Vannajan Sanghiran, Rungrotmongkol, Thanyada, Fey, Natalie, Spencer, James, Mulholland, Adrian J
Format:	Artikel
Sprache:	eng
Schlagworte:	Alkaline phosphatase Alkaline Phosphatase - chemistry Anti-Bacterial Agents - chemistry Antibiotics Bacterial Proteins - chemistry Chemistry Chemistry, Multidisciplinary Colistin - chemistry Density functional theory Drug Resistance, Bacterial Enzymes Ethanolamines - chemistry Lipid A - chemistry Lipids Molecular dynamics Molecular Dynamics Simulation Physical Sciences Science & Technology Zinc - chemistry
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Zusammenfassung:	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. Simulations show the mono-zinc form of MCR to be stable and competent for covalent phospho(ethanolamine) intermediate formation.
ISSN:	1359-7345 1364-548X
DOI:	10.1039/d0cc02520h