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Toxin release by conditional remodelling of ParDE1 from Mycobacterium tuberculosis leads to gyrase inhibition

Lookup NU author(s): Dr Jon Marles-WrightORCiD

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


Abstract

© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.Mycobacterium tuberculosis, the causative agent of tuberculosis, is a growing threat to global health, with recent efforts towards its eradication being reversed in the wake of the COVID-19 pandemic. Increasing resistance to gyrase-targeting second-line fluoroquinolone antibiotics indicates the necessity to develop both novel therapeutics and our understanding of M. tuberculosis growth during infection. ParDE toxin–antitoxin systems also target gyrase and are regulated in response to both host-associated and drug-induced stress during infection. Here, we present microbiological, biochemical, structural, and biophysical analyses exploring the ParDE1 and ParDE2 systems of M. tuberculosis H37Rv. The structures reveal conserved modes of toxin–antitoxin recognition, with complex-specific interactions. ParDE1 forms a novel heterohexameric ParDE complex, supported by antitoxin chains taking on two distinct folds. Curiously, ParDE1 exists in solution as a dynamic equilibrium between heterotetrameric and heterohexameric complexes. Conditional remodelling into higher order complexes can be thermally driven in vitro. Remodelling induces toxin release, tracked through concomitant inhibition and poisoning of gyrase activity. Our work aids our understanding of gyrase inhibition, allowing wider exploration of toxin–antitoxin systems as inspiration for potential therapeutic agents.


Publication metadata

Author(s): Beck IN, Arrowsmith TJ, Grobbelaar MJ, Bromley EHC, Marles-Wright J, Blower TR

Publication type: Article

Publication status: Published

Journal: Nucleic Acids Research

Year: 2024

Volume: 52

Issue: 4

Pages: 1909-1929

Online publication date: 19/12/2023

Acceptance date: 12/12/2023

Date deposited: 19/03/2024

ISSN (print): 0305-1048

ISSN (electronic): 1362-4962

Publisher: Oxford University Press

URL: https://doi.org/10.1093/nar/gkad1220

DOI: 10.1093/nar/gkad1220

Data Access Statement: The crystal structures of ParDE1 and ParDE2 have been deposited in the Protein Data Bank under accession numbers 8C24 and 8C26, respectively. All other data needed to evaluate the conclusions in the paper are present in the paper and/or Supplementary Data.

PubMed id: 38113275


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Funding

Funder referenceFunder name
BB/M011186/1
BBSRC
EP/S022791/1EPSRC
EPSRC

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