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

Allen P. Zinkle, Mariana Bunoro Batista, Carmen M. Herrera, Satchal K. Erramilli, Brian Kloss, Khuram U. Ashraf, Kamil Nosol, Guozhi Zhang, Rosemary J. Cater, Michael T. Marty, Anthony A. Kossiakoff, M. Stephen Trent (), Rie Nygaard (), Phillip J. Stansfeld () and Filippo Mancia ()
Additional contact information
Allen P. Zinkle: Columbia University Irving Medical Center, Department of Physiology and Cellular Biophysics
Mariana Bunoro Batista: University of Warwick, School of Life Sciences and Department of Chemistry
Carmen M. Herrera: University of Georgia, Department of Infectious Diseases, College of Veterinary Medicine
Satchal K. Erramilli: University of Chicago, Department of Biochemistry and Molecular Biology
Brian Kloss: Columbia University Irving Medical Center, Department of Physiology and Cellular Biophysics
Khuram U. Ashraf: Columbia University Irving Medical Center, Department of Physiology and Cellular Biophysics
Kamil Nosol: University of Chicago, Department of Biochemistry and Molecular Biology
Guozhi Zhang: University of Arizona, Department of Chemistry and Biochemistry
Rosemary J. Cater: Columbia University Irving Medical Center, Department of Physiology and Cellular Biophysics
Michael T. Marty: University of Arizona, Department of Chemistry and Biochemistry
Anthony A. Kossiakoff: University of Chicago, Department of Biochemistry and Molecular Biology
M. Stephen Trent: University of Georgia, Department of Infectious Diseases, College of Veterinary Medicine
Rie Nygaard: Columbia University Irving Medical Center, Department of Physiology and Cellular Biophysics
Phillip J. Stansfeld: University of Warwick, School of Life Sciences and Department of Chemistry
Filippo Mancia: Columbia University Irving Medical Center, Department of Physiology and Cellular Biophysics

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-65515-3

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