| Structural highlights
Function
MCR1_ECOLX Probably catalyzes the addition of a phosphoethanolamine moiety to lipid A. Phosphoethanolamine modification of lipid A gives polymyxin resistance (PubMed:26603172).[1] Confers resistance to polymyxin-type antibiotics; expression of the Mcr-1 protein in E.coli increases colistin and polymyxin B minimal inhibitory concentration (MIC) from 0.5 mg/ml to 2.0 mg/ml. The pHNSHP45 plasmid can transfer efficiently (0.1 to 0.001) to other E.coli strains by conjugation and increases polymxin MIC by 8- to 16-fold; it may not require selective pressure to be maintained in the cell. When transformed into K.pneumoniae or P.aeruginosa it also increases polymxin MIC 8- to 16-fold. In a murine (BALB/c mice) thigh infection study using an mcr1-encoding plasmid isolated from a human patient, the plasmid confers in vivo protection against colistin (PubMed:26603172).[2]
Publication Abstract from PubMed
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 A 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.
Mechanistic basis of antimicrobial resistance mediated by the phosphoethanolamine transferase MCR-1.,Zinkle AP, Batista MB, Herrera CM, Erramilli SK, Kloss B, Ashraf KU, Nosol K, Zhang G, Cater RJ, Marty MT, Kossiakoff AA, Trent MS, Nygaard R, Stansfeld PJ, Mancia F Nat Commun. 2025 Nov 26;16(1):10516. doi: 10.1038/s41467-025-65515-3. PMID:41298376[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Liu YY, Wang Y, Walsh TR, Yi LX, Zhang R, Spencer J, Doi Y, Tian G, Dong B, Huang X, Yu LF, Gu D, Ren H, Chen X, Lv L, He D, Zhou H, Liang Z, Liu JH, Shen J. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect Dis. 2016 Feb;16(2):161-8. doi: 10.1016/S1473-3099(15)00424-7. Epub, 2015 Nov 19. PMID:26603172 doi:http://dx.doi.org/10.1016/S1473-3099(15)00424-7
- ↑ Liu YY, Wang Y, Walsh TR, Yi LX, Zhang R, Spencer J, Doi Y, Tian G, Dong B, Huang X, Yu LF, Gu D, Ren H, Chen X, Lv L, He D, Zhou H, Liang Z, Liu JH, Shen J. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect Dis. 2016 Feb;16(2):161-8. doi: 10.1016/S1473-3099(15)00424-7. Epub, 2015 Nov 19. PMID:26603172 doi:http://dx.doi.org/10.1016/S1473-3099(15)00424-7
- ↑ Zinkle AP, Batista MB, Herrera CM, Erramilli SK, Kloss B, Ashraf KU, Nosol K, Zhang G, Cater RJ, Marty MT, Kossiakoff AA, Trent MS, Nygaard R, Stansfeld PJ, Mancia F. Mechanistic basis of antimicrobial resistance mediated by the phosphoethanolamine transferase MCR-1. Nat Commun. 2025 Nov 26;16(1):10516. PMID:41298376 doi:10.1038/s41467-025-65515-3
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