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

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.

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Journal
Nature Communications
Published
2025-11-26
DOI
https://doi.org/10.1038/s41467-025-65515-3
Primary Topic
Antibiotic Resistance in Bacteria
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article
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article

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

Khuram U. Ashraf, Allen P. Zinkle, Rosemary J. Cater, Filippo Mancia et al.
Nature Communications
Antibiotic Resistance in Bacteria
article

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

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

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.

Nature CommunicationsVol. 16(1)
University of Arizona (US), The University of Queensland (AU), University of Georgia (US), Cornell University (US), Columbia University Irving Medical Center (US), University of Warwick (GB), University of Chicago (US)
Openalex Percentile: Top 68%
Antibiotic Resistance in Bacteria
DOIOpen Access PDFOpenAlex
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