Efficacy of epetraborole against Mycobacterium abscessus is increased with norvaline.

Mycobacterium abscessus is the most common rapidly growing non-tuberculous mycobacteria to cause pulmonary disease in patients with impaired lung function such as cystic fibrosis. M. abscessus displays high intrinsic resistance to common antibiotics and inducible resistance to macrolides like clarit...

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Autores principales:	Jaryd R Sullivan, Andréanne Lupien, Elias Kalthoff, Claire Hamela, Lorne Taylor, Kim A Munro, T Martin Schmeing, Laurent Kremer, Marcel A Behr
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/00b163bb87694ef3a91a7c1a1e0809a3
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spelling	oai:doaj.org-article:00b163bb87694ef3a91a7c1a1e0809a32021-12-02T20:00:02ZEfficacy of epetraborole against Mycobacterium abscessus is increased with norvaline.1553-73661553-737410.1371/journal.ppat.1009965https://doaj.org/article/00b163bb87694ef3a91a7c1a1e0809a32021-10-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.1009965https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Mycobacterium abscessus is the most common rapidly growing non-tuberculous mycobacteria to cause pulmonary disease in patients with impaired lung function such as cystic fibrosis. M. abscessus displays high intrinsic resistance to common antibiotics and inducible resistance to macrolides like clarithromycin. As such, M. abscessus is clinically resistant to the entire regimen of front-line M. tuberculosis drugs, and treatment with antibiotics that do inhibit M. abscessus in the lab results in cure rates of 50% or less. Here, we identified epetraborole (EPT) from the MMV pandemic response box as an inhibitor against the essential protein leucyl-tRNA synthetase (LeuRS) in M. abscessus. EPT protected zebrafish from lethal M. abscessus infection and did not induce self-resistance nor against clarithromycin. Contrary to most antimycobacterials, the whole-cell activity of EPT was greater against M. abscessus than M. tuberculosis, but crystallographic and equilibrium binding data showed that EPT binds LeuRSMabs and LeuRSMtb with similar residues and dissociation constants. Since EPT-resistant M. abscessus mutants lost LeuRS editing activity, these mutants became susceptible to misaminoacylation with leucine mimics like the non-proteinogenic amino acid norvaline. Proteomic analysis revealed that when M. abscessus LeuRS mutants were fed norvaline, leucine residues in proteins were replaced by norvaline, inducing the unfolded protein response with temporal changes in expression of GroEL chaperonins and Clp proteases. This supports our in vitro data that supplementation of media with norvaline reduced the emergence of EPT mutants in both M. abscessus and M. tuberculosis. Furthermore, the combination of EPT and norvaline had improved in vivo efficacy compared to EPT in a murine model of M. abscessus infection. Our results emphasize the effectiveness of EPT against the clinically relevant cystic fibrosis pathogen M. abscessus, and these findings also suggest norvaline adjunct therapy with EPT could be beneficial for M. abscessus and other mycobacterial infections like tuberculosis.Jaryd R SullivanAndréanne LupienElias KalthoffClaire HamelaLorne TaylorKim A MunroT Martin SchmeingLaurent KremerMarcel A BehrPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 17, Iss 10, p e1009965 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Jaryd R Sullivan Andréanne Lupien Elias Kalthoff Claire Hamela Lorne Taylor Kim A Munro T Martin Schmeing Laurent Kremer Marcel A Behr Efficacy of epetraborole against Mycobacterium abscessus is increased with norvaline.
description	Mycobacterium abscessus is the most common rapidly growing non-tuberculous mycobacteria to cause pulmonary disease in patients with impaired lung function such as cystic fibrosis. M. abscessus displays high intrinsic resistance to common antibiotics and inducible resistance to macrolides like clarithromycin. As such, M. abscessus is clinically resistant to the entire regimen of front-line M. tuberculosis drugs, and treatment with antibiotics that do inhibit M. abscessus in the lab results in cure rates of 50% or less. Here, we identified epetraborole (EPT) from the MMV pandemic response box as an inhibitor against the essential protein leucyl-tRNA synthetase (LeuRS) in M. abscessus. EPT protected zebrafish from lethal M. abscessus infection and did not induce self-resistance nor against clarithromycin. Contrary to most antimycobacterials, the whole-cell activity of EPT was greater against M. abscessus than M. tuberculosis, but crystallographic and equilibrium binding data showed that EPT binds LeuRSMabs and LeuRSMtb with similar residues and dissociation constants. Since EPT-resistant M. abscessus mutants lost LeuRS editing activity, these mutants became susceptible to misaminoacylation with leucine mimics like the non-proteinogenic amino acid norvaline. Proteomic analysis revealed that when M. abscessus LeuRS mutants were fed norvaline, leucine residues in proteins were replaced by norvaline, inducing the unfolded protein response with temporal changes in expression of GroEL chaperonins and Clp proteases. This supports our in vitro data that supplementation of media with norvaline reduced the emergence of EPT mutants in both M. abscessus and M. tuberculosis. Furthermore, the combination of EPT and norvaline had improved in vivo efficacy compared to EPT in a murine model of M. abscessus infection. Our results emphasize the effectiveness of EPT against the clinically relevant cystic fibrosis pathogen M. abscessus, and these findings also suggest norvaline adjunct therapy with EPT could be beneficial for M. abscessus and other mycobacterial infections like tuberculosis.
format	article
author	Jaryd R Sullivan Andréanne Lupien Elias Kalthoff Claire Hamela Lorne Taylor Kim A Munro T Martin Schmeing Laurent Kremer Marcel A Behr
author_facet	Jaryd R Sullivan Andréanne Lupien Elias Kalthoff Claire Hamela Lorne Taylor Kim A Munro T Martin Schmeing Laurent Kremer Marcel A Behr
author_sort	Jaryd R Sullivan
title	Efficacy of epetraborole against Mycobacterium abscessus is increased with norvaline.
title_short	Efficacy of epetraborole against Mycobacterium abscessus is increased with norvaline.
title_full	Efficacy of epetraborole against Mycobacterium abscessus is increased with norvaline.
title_fullStr	Efficacy of epetraborole against Mycobacterium abscessus is increased with norvaline.
title_full_unstemmed	Efficacy of epetraborole against Mycobacterium abscessus is increased with norvaline.
title_sort	efficacy of epetraborole against mycobacterium abscessus is increased with norvaline.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/00b163bb87694ef3a91a7c1a1e0809a3
work_keys_str_mv	AT jarydrsullivan efficacyofepetraboroleagainstmycobacteriumabscessusisincreasedwithnorvaline AT andreannelupien efficacyofepetraboroleagainstmycobacteriumabscessusisincreasedwithnorvaline AT eliaskalthoff efficacyofepetraboroleagainstmycobacteriumabscessusisincreasedwithnorvaline AT clairehamela efficacyofepetraboroleagainstmycobacteriumabscessusisincreasedwithnorvaline AT lornetaylor efficacyofepetraboroleagainstmycobacteriumabscessusisincreasedwithnorvaline AT kimamunro efficacyofepetraboroleagainstmycobacteriumabscessusisincreasedwithnorvaline AT tmartinschmeing efficacyofepetraboroleagainstmycobacteriumabscessusisincreasedwithnorvaline AT laurentkremer efficacyofepetraboroleagainstmycobacteriumabscessusisincreasedwithnorvaline AT marcelabehr efficacyofepetraboroleagainstmycobacteriumabscessusisincreasedwithnorvaline
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Efficacy of epetraborole against Mycobacterium abscessus is increased with norvaline.

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