Identification of KasA as the cellular target of an anti-tubercular scaffold

Katherine A. Abrahams; Chun-Wa Chung; Sonja Ghidelli-Disse; Joaquín Rullas; María José Rebollo-López; Sudagar S. Gurcha; Jonathan A.G. Cox; Alfonso Mendoza; Elena Jiménez-Navarro; María Santos Martínez-Martínez; Margarete Neu; Anthony Shillings; Paul Homes; Argyrides Argyrou; Ruth Casanueva; Nicholas J. Loman; Patrick J. Moynihan; Joël Lelièvre; Carolyn Selenski; Matthew Axtman; Laurent Kremer; Marcus Bantscheff; Iñigo Angulo-Barturen; Mónica Cacho Izquierdo; Nicholas C. Cammack; Gerard Drewes; Lluis Ballell; David Barros; Gurdyal S. Besra; Robert H. Bates

doi:10.1038/ncomms12581

Identification of KasA as the cellular target of an anti-tubercular scaffold

Katherine A. Abrahams, Chun-Wa Chung, Sonja Ghidelli-Disse, Joaquín Rullas, María José Rebollo-López, Sudagar S. Gurcha, Jonathan A.G. Cox, Alfonso Mendoza, Elena Jiménez-Navarro, María Santos Martínez-Martínez, Margarete Neu, Anthony Shillings, Paul Homes, Argyrides Argyrou, Ruth Casanueva, Nicholas J. Loman, Patrick J. Moynihan, Joël Lelièvre, Carolyn Selenski, Matthew AxtmanLaurent Kremer, Marcus Bantscheff, Iñigo Angulo-Barturen, Mónica Cacho Izquierdo, Nicholas C. Cammack, Gerard Drewes, Lluis Ballell, David Barros, Gurdyal S. Besra, Robert H. Bates

Research output: Contribution to journal › Article › peer-review

Abstract

Phenotypic screens for bactericidal compounds are starting to yield promising hits against tuberculosis. In this regard, whole-genome sequencing of spontaneous resistant mutants generated against an indazole sulfonamide (GSK3011724A) identifies several specific single-nucleotide polymorphisms in the essential Mycobacterium tuberculosis β-ketoacyl synthase (kas) A gene. Here, this genomic-based target assignment is confirmed by biochemical assays, chemical proteomics and structural resolution of a KasA-GSK3011724A complex by X-ray crystallography. Finally, M. tuberculosis GSK3011724A-resistant mutants increase the in vitro minimum inhibitory concentration and the in vivo 99% effective dose in mice, establishing in vitro and in vivo target engagement. Surprisingly, the lack of target engagement of the related β-ketoacyl synthases (FabH and KasB) suggests a different mode of inhibition when compared with other Kas inhibitors of fatty acid biosynthesis in bacteria. These results clearly identify KasA as the biological target of GSK3011724A and validate this enzyme for further drug discovery efforts against tuberculosis.

Original language	English
Article number	12581
Number of pages	13
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms12581
Publication status	Published - 1 Sept 2016

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This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this
article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

Funding: EU FP7 (261378); Bill & Melinda Gates Foundation (OPP1095631; and MRC (MR/K012118/1).

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Journal Article

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10.1038/ncomms12581Licence: CC BY 3.0

Identification of KasA as the cellular target of an anti-tubercular scaffold
This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
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Abrahams, K. A., Chung, C.-W., Ghidelli-Disse, S., Rullas, J., Rebollo-López, M. J., Gurcha, S. S., Cox, J. A. G., Mendoza, A., Jiménez-Navarro, E., Martínez-Martínez, M. S., Neu, M., Shillings, A., Homes, P., Argyrou, A., Casanueva, R., Loman, N. J., Moynihan, P. J., Lelièvre, J., Selenski, C., ... Bates, R. H. (2016). Identification of KasA as the cellular target of an anti-tubercular scaffold. Nature Communications, 7, Article 12581. https://doi.org/10.1038/ncomms12581

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title = "Identification of KasA as the cellular target of an anti-tubercular scaffold",

abstract = "Phenotypic screens for bactericidal compounds are starting to yield promising hits against tuberculosis. In this regard, whole-genome sequencing of spontaneous resistant mutants generated against an indazole sulfonamide (GSK3011724A) identifies several specific single-nucleotide polymorphisms in the essential Mycobacterium tuberculosis β-ketoacyl synthase (kas) A gene. Here, this genomic-based target assignment is confirmed by biochemical assays, chemical proteomics and structural resolution of a KasA-GSK3011724A complex by X-ray crystallography. Finally, M. tuberculosis GSK3011724A-resistant mutants increase the in vitro minimum inhibitory concentration and the in vivo 99% effective dose in mice, establishing in vitro and in vivo target engagement. Surprisingly, the lack of target engagement of the related β-ketoacyl synthases (FabH and KasB) suggests a different mode of inhibition when compared with other Kas inhibitors of fatty acid biosynthesis in bacteria. These results clearly identify KasA as the biological target of GSK3011724A and validate this enzyme for further drug discovery efforts against tuberculosis.",

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author = "Abrahams, {Katherine A.} and Chun-Wa Chung and Sonja Ghidelli-Disse and Joaqu{\'i}n Rullas and Rebollo-L{\'o}pez, {Mar{\'i}a Jos{\'e}} and Gurcha, {Sudagar S.} and Cox, {Jonathan A.G.} and Alfonso Mendoza and Elena Jim{\'e}nez-Navarro and Mart{\'i}nez-Mart{\'i}nez, {Mar{\'i}a Santos} and Margarete Neu and Anthony Shillings and Paul Homes and Argyrides Argyrou and Ruth Casanueva and Loman, {Nicholas J.} and Moynihan, {Patrick J.} and Jo{\"e}l Leli{\`e}vre and Carolyn Selenski and Matthew Axtman and Laurent Kremer and Marcus Bantscheff and I{\~n}igo Angulo-Barturen and Izquierdo, {M{\'o}nica Cacho} and Cammack, {Nicholas C.} and Gerard Drewes and Lluis Ballell and David Barros and Besra, {Gurdyal S.} and Bates, {Robert H.}",

note = "This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article{\textquoteright}s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ Funding: EU FP7 (261378); Bill & Melinda Gates Foundation (OPP1095631; and MRC (MR/K012118/1).",

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Abrahams, KA, Chung, C-W, Ghidelli-Disse, S, Rullas, J, Rebollo-López, MJ, Gurcha, SS, Cox, JAG, Mendoza, A, Jiménez-Navarro, E, Martínez-Martínez, MS, Neu, M, Shillings, A, Homes, P, Argyrou, A, Casanueva, R, Loman, NJ, Moynihan, PJ, Lelièvre, J, Selenski, C, Axtman, M, Kremer, L, Bantscheff, M, Angulo-Barturen, I, Izquierdo, MC, Cammack, NC, Drewes, G, Ballell, L, Barros, D, Besra, GS & Bates, RH 2016, 'Identification of KasA as the cellular target of an anti-tubercular scaffold', Nature Communications, vol. 7, 12581. https://doi.org/10.1038/ncomms12581

TY - JOUR

T1 - Identification of KasA as the cellular target of an anti-tubercular scaffold

AU - Abrahams, Katherine A.

AU - Chung, Chun-Wa

AU - Ghidelli-Disse, Sonja

AU - Rullas, Joaquín

AU - Rebollo-López, María José

AU - Gurcha, Sudagar S.

AU - Cox, Jonathan A.G.

AU - Mendoza, Alfonso

AU - Jiménez-Navarro, Elena

AU - Martínez-Martínez, María Santos

AU - Neu, Margarete

AU - Shillings, Anthony

AU - Homes, Paul

AU - Argyrou, Argyrides

AU - Casanueva, Ruth

AU - Loman, Nicholas J.

AU - Moynihan, Patrick J.

AU - Lelièvre, Joël

AU - Selenski, Carolyn

AU - Axtman, Matthew

AU - Kremer, Laurent

AU - Bantscheff, Marcus

AU - Angulo-Barturen, Iñigo

AU - Izquierdo, Mónica Cacho

AU - Cammack, Nicholas C.

AU - Drewes, Gerard

AU - Ballell, Lluis

AU - Barros, David

AU - Besra, Gurdyal S.

AU - Bates, Robert H.

N1 - This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ Funding: EU FP7 (261378); Bill & Melinda Gates Foundation (OPP1095631; and MRC (MR/K012118/1).

PY - 2016/9/1

Y1 - 2016/9/1

N2 - Phenotypic screens for bactericidal compounds are starting to yield promising hits against tuberculosis. In this regard, whole-genome sequencing of spontaneous resistant mutants generated against an indazole sulfonamide (GSK3011724A) identifies several specific single-nucleotide polymorphisms in the essential Mycobacterium tuberculosis β-ketoacyl synthase (kas) A gene. Here, this genomic-based target assignment is confirmed by biochemical assays, chemical proteomics and structural resolution of a KasA-GSK3011724A complex by X-ray crystallography. Finally, M. tuberculosis GSK3011724A-resistant mutants increase the in vitro minimum inhibitory concentration and the in vivo 99% effective dose in mice, establishing in vitro and in vivo target engagement. Surprisingly, the lack of target engagement of the related β-ketoacyl synthases (FabH and KasB) suggests a different mode of inhibition when compared with other Kas inhibitors of fatty acid biosynthesis in bacteria. These results clearly identify KasA as the biological target of GSK3011724A and validate this enzyme for further drug discovery efforts against tuberculosis.

AB - Phenotypic screens for bactericidal compounds are starting to yield promising hits against tuberculosis. In this regard, whole-genome sequencing of spontaneous resistant mutants generated against an indazole sulfonamide (GSK3011724A) identifies several specific single-nucleotide polymorphisms in the essential Mycobacterium tuberculosis β-ketoacyl synthase (kas) A gene. Here, this genomic-based target assignment is confirmed by biochemical assays, chemical proteomics and structural resolution of a KasA-GSK3011724A complex by X-ray crystallography. Finally, M. tuberculosis GSK3011724A-resistant mutants increase the in vitro minimum inhibitory concentration and the in vivo 99% effective dose in mice, establishing in vitro and in vivo target engagement. Surprisingly, the lack of target engagement of the related β-ketoacyl synthases (FabH and KasB) suggests a different mode of inhibition when compared with other Kas inhibitors of fatty acid biosynthesis in bacteria. These results clearly identify KasA as the biological target of GSK3011724A and validate this enzyme for further drug discovery efforts against tuberculosis.

KW - Journal Article

UR - https://www.nature.com/articles/ncomms12581

UR - https://www.ebi.ac.uk/pdbe/entry/pdb/5ld8

U2 - 10.1038/ncomms12581

DO - 10.1038/ncomms12581

M3 - Article

C2 - 27581223

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 12581

ER -

Identification of KasA as the cellular target of an anti-tubercular scaffold

Abstract

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