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Lookup NU author(s): Dr Jason Woodgate, Felaine Sumang, Mary Salliss, Emeritus Professor Alan Ward, Professor Nikolay ZenkinORCiD, Emeritus Professor Jeff Errington, Dr Yousef Dashti
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
© 2024 The Authors. Published by American Chemical Society. Persiathiacin A is a novel thiopeptide antibiotic produced by Actinokineospora species UTMC 2448. It has potent activity against methicillin-resistant Staphylococcus aureus (MRSA) and Mycobacterium tuberculosis. Thiopeptides, including persiathiacin A, exhibit antibacterial activity by inhibiting protein synthesis. In this study, we characterize the mechanism of action of persiathiacin A and investigate how resistance to this antibiotic can emerge. In vitro assays revealed that persiathiacin A inhibits translation elongation, leading to ribosome stalling. Genetic analysis of resistant Bacillus subtilis mutants identified mutations primarily in the rplK gene encoding ribosomal protein L11, which is the binding site for other 26-membered macrocycle-containing thiopeptides. The resistant mutants showed growth impairment and an increased lag time, even in the absence of persiathiacin. Comparative proteomic analysis of a resistant mutant versus the parental strain revealed multiple changes, indicative of negative effects on protein synthesis. Thus, although persiathiacin-resistant mutants can arise readily by the loss of L11 function, it is likely that such mutants would be severely compromised in pathogenesis. Furthermore, bioinformatics analysis identified differences in the key amino acids within the thiopeptide-binding region of L11 in the persiathiacin producer. These probably prevent the antibiotic from associating with its target, providing a mechanism for self-resistance.
Author(s): Woodgate J, Sumang FA, Salliss ME, Belousoff M, Ward AC, Challis GL, Zenkin N, Errington J, Dashti Y
Publication type: Article
Publication status: Published
Journal: ACS Infectious Diseases
Year: 2024
Pages: Epub ahead of print
Online publication date: 09/12/2024
Acceptance date: 11/11/2024
Date deposited: 06/01/2025
ISSN (electronic): 2373-8227
Publisher: American Chemical Society
URL: https://doi.org/10.1021/acsinfecdis.4c00503
DOI: 10.1021/acsinfecdis.4c00503
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