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Lookup NU author(s): Dr Victor Hernandez-RocamoraORCiD, Professor Waldemar Vollmer
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2024 The Authors. Published by American Chemical SocietyThe rapid spread of drug-resistant pathogens and the declining discovery of new antibiotics have created a global health crisis and heightened interest in the search for novel antibiotics. Beyond their discovery, elucidating mechanisms of action has necessitated new approaches, especially for antibiotics that interact with lipidic substrates and membrane proteins. Here, we develop a methodology for real-time reaction monitoring of the activities of two bacterial membrane phosphatases, UppP and PgpB. We then show how we can inhibit their activities using existing and newly discovered antibiotics such as bacitracin and teixobactin. Additionally, we found that the UppP dimer is stabilized by phosphatidylethanolamine, which, unexpectedly, enhanced the speed of substrate processing. Overall, our results demonstrate the potential of native mass spectrometry for real-time biosynthetic reaction monitoring of membrane enzymes, as well as their in situ inhibition and cofactor binding, to inform the mode of action of emerging antibiotics.
Author(s): Oluwole AO, Hernandez-Rocamora VM, Cao Y, Li X, Vollmer W, Robinson CV, Bolla JR
Publication type: Article
Publication status: Published
Journal: Journal of the American Chemical Society
Year: 2024
Volume: 146
Issue: 10
Pages: 7007–7017
Print publication date: 13/03/2024
Online publication date: 01/03/2024
Acceptance date: 16/02/2024
Date deposited: 18/03/2024
ISSN (print): 0002-7863
ISSN (electronic): 1520-5126
Publisher: American Chemical Society
URL: https://doi.org/10.1021/jacs.4c00081
DOI: 10.1021/jacs.4c00081
PubMed id: 38428018
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