PUBLICATION
Dysregulation of Mycobacterium marinum ESX-5 Secretion by Novel 1,2,4-oxadiazoles
- Authors
- Ho, V.Q.T., Rong, M.K., Habjan, E., Bommer, S.D., Pham, T.V., Piersma, S.R., Bitter, W., Ruijter, E., Speer, A.
- ID
- ZDB-PUB-230226-46
- Date
- 2023
- Source
- Biomolecules 13(2): (Journal)
- Registered Authors
- Bitter, Wilbert
- Keywords
- ESX-5, Mycobacterium marinum, mycobacteria, protein secretion, type VII secretion
- MeSH Terms
-
- Animals
- Bacterial Proteins/metabolism
- Lipase/metabolism
- Mycobacterium marinum*/genetics
- Mycobacterium marinum*/metabolism
- Mycobacterium tuberculosis*/metabolism
- Type VII Secretion Systems*/genetics
- Type VII Secretion Systems*/metabolism
- Virulence
- Zebrafish/metabolism
- PubMed
- 36830581 Full text @ Biomolecules
Citation
Ho, V.Q.T., Rong, M.K., Habjan, E., Bommer, S.D., Pham, T.V., Piersma, S.R., Bitter, W., Ruijter, E., Speer, A. (2023) Dysregulation of Mycobacterium marinum ESX-5 Secretion by Novel 1,2,4-oxadiazoles. Biomolecules. 13(2):.
Abstract
The ESX-5 secretion system is essential for the viability and virulence of slow-growing pathogenic mycobacterial species. In this study, we identified a 1,2,4-oxadiazole derivative as a putative effector of the ESX-5 secretion system. We confirmed that this 1,2,4-oxadiazole and several newly synthesized derivatives inhibited the ESX-5-dependent secretion of active lipase LipY by Mycobacterium marinum (M. marinum). Despite reduced lipase activity, we did not observe a defect in LipY secretion itself. Moreover, we found that several other ESX-5 substrates, especially the high molecular-weight PE_PGRS MMAR_5294, were even more abundantly secreted by M. marinum treated with several 1,2,4-oxadiazoles. Analysis of M. marinum grown in the presence of different oxadiazole derivatives revealed that the secretion of LipY and the induction of PE_PGRS secretion were, in fact, two independent phenotypes, as we were able to identify structural features in the compounds that specifically induced only one of these phenotypes. Whereas the three most potent 1,2,4-oxadiazoles displayed only a mild effect on the growth of M. marinum or M. tuberculosis in culture, these compounds significantly reduced bacterial burden in M. marinum-infected zebrafish models. In conclusion, we report a 1,2,4-oxadiazole scaffold that dysregulates ESX-5 protein secretion.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping