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Real-Time Biosynthetic Reaction Monitoring Informs the Mechanism of Action of Antibiotics

Lookup NU author(s): Dr Victor Hernandez-RocamoraORCiD, Professor Waldemar Vollmer

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 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.


Publication metadata

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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Funding

Funder referenceFunder name
BB/R017409/1Biotechnology and Biological Sciences Research Council (BBSRC)
BB/W005557/1
BBSRC
Medical Research Council (MRC)
MR/V028839/1
Royal Society
URF\R1\211567

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