Journal Article

Mechanistic basis of antimicrobial resistance mediated by the phosphoethanolamine transferase MCR-1

Marty, Michael T., Nygaard, Rie, Kossiakoff, Anthony A., Zinkle, Allen P., Cater, Rosemary J., Batista, Mariana Bunoro, Herrera, Carmen M., Kloss, Brian, Mancia, Filippo, Ashraf, Khuram U., Erramilli, Satchal K., Stansfeld, Phillip J., Trent, M. Stephen, Zhang, Guozhi, Nosol, Kamil

2025

Overview

Polymyxins are used to treat infections caused by multidrug-resistant Gram-negative bacteria. They are cationic peptides that target the negatively charged lipid A component of lipopolysaccharides, disrupting the outer membrane and lysing the cell. Polymyxin resistance is conferred by inner-membrane enzymes, such as phosphoethanolamine transferases, which add positively charged phosphoethanolamine to lipid A. Here, we present the structure of MCR-1, a plasmid-encoded phosphoethanolamine transferase, in its liganded form. The phosphatidylethanolamine donor substrate is bound near the active site in the periplasmic domain, and lipid A is bound over 20 Å away, within the transmembrane region. Integrating structural, biochemical, and drug-resistance data with computational analyses, we propose a two-state model in which the periplasmic domain rotates to bring the active site to lipid A, near the preferential phosphate modification site for MCR-1. This enzymatic mechanism may be generally applicable to other phosphoform transferases with large, globular soluble domains. Bacterial resistance to polymyxin antibiotics is conferred by enzymes such as phosphoethanolamine transferases, which add positively charged phosphoethanolamine to lipid A. Here, the authors present the structure of one such enzyme in its liganded form, and propose an enzymatic mechanism that may be generally applicable to other phosphoform transferases.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/28 / 631/326/22/1434 / 631/45/607/1172 / 631/535/1258/1259 / 82/16 / 82/83 / Anti-Bacterial Agents - pharmacology / Antibiotics / Antimicrobial resistance / Bacteria / Catalytic Domain / Cationic peptides / Chromatography / Colistin - pharmacology / Crystallography, X-Ray / Detergents / Drug resistance / Drug Resistance, Bacterial / E coli / Enzymes / Escherichia coli - drug effects / Escherichia coli - enzymology / Escherichia coli - genetics / Escherichia coli Proteins - chemistry / Escherichia coli Proteins - genetics / Escherichia coli Proteins - metabolism / Ethanolaminephosphotransferase - chemistry / Ethanolaminephosphotransferase - genetics / Ethanolaminephosphotransferase - metabolism / Ethanolamines - metabolism / Gram-negative bacteria / Humanities and Social Sciences / Lipid A / Lipid A - chemistry / Lipid A - metabolism / Lipids / Lipopolysaccharides / Membranes / Models, Molecular / multidisciplinary / Multidrug resistance / Peptides / Phosphatidylethanolamine / Phosphatidylethanolamines - metabolism / Polymyxins / Polymyxins - pharmacology / Proteins / Science / Science (multidisciplinary) / Transferases (Other Substituted Phosphate Groups) - chemistry / Transferases (Other Substituted Phosphate Groups) - genetics / Transferases (Other Substituted Phosphate Groups) - metabolism