Inhibiting mycobacterial tryptophan synthase by targeting the inter-subunit interface

Katherine A. Abrahams, Jonathan A.G. Cox, Klaus Fütterer, Joaquín Rullas, Fátima Ortega-Muro, Nicholas J. Loman, Patrick J. Moynihan, Esther Pérez-Herrán, Elena Jiménez, Jorge Esquivias, David Barros, Lluís Ballell, Carlos Alemparte*, Gurdyal S. Besra

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Drug discovery efforts against the pathogen Mycobacterium tuberculosis (Mtb) have been advanced through phenotypic screens of extensive compound libraries. Such a screen revealed sulfolane 1 and indoline-5-sulfonamides 2 and 3 as potent inhibitors of mycobacterial growth. Optimization in the sulfolane series led to compound 4, which has proven activity in an in vivo murine model of Mtb infection. Here we identify the target and mode of inhibition of these compounds based on whole genome sequencing of spontaneous resistant mutants, which identified mutations locating to the essential α- and β-subunits of tryptophan synthase. Over-expression studies confirmed tryptophan synthase as the biological target. Biochemical techniques probed the mechanism of inhibition, revealing the mutant enzyme complex incurs a fitness cost but does not prevent inhibitor binding. Mapping of the resistance conferring mutations onto a low-resolution crystal structure of Mtb tryptophan synthase showed they locate to the interface between the α- and β-subunits. The discovery of anti-tubercular agents inhibiting tryptophan synthase highlights the therapeutic potential of this enzyme and draws attention to the prospect of other amino acid biosynthetic pathways as future Mtb drug targets.

Original languageEnglish
Article number9430
Number of pages15
JournalScientific Reports
Volume7
DOIs
Publication statusPublished - 25 Aug 2017

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Tryptophan Synthase
Mycobacterium tuberculosis
Growth Inhibitors
Mutation
Mycobacterium Infections
Biosynthetic Pathways
Sulfonamides
Enzymes
Drug Discovery
Libraries
Genome
Amino Acids
Costs and Cost Analysis
Pharmaceutical Preparations

Bibliographical note

© The Author(s) 2017. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Funding: FP7-2007-2013 (261378); MRC (MR/K012118/1); and Wellcome Trust (081569/Z/06/Z).

Keywords

  • microbiology
  • Target identification
  • X-ray crystallography
  • target validation

Cite this

Abrahams, K. A., Cox, J. A. G., Fütterer, K., Rullas, J., Ortega-Muro, F., Loman, N. J., ... Besra, G. S. (2017). Inhibiting mycobacterial tryptophan synthase by targeting the inter-subunit interface. Scientific Reports, 7, [9430]. https://doi.org/10.1038/s41598-017-09642-y
Abrahams, Katherine A. ; Cox, Jonathan A.G. ; Fütterer, Klaus ; Rullas, Joaquín ; Ortega-Muro, Fátima ; Loman, Nicholas J. ; Moynihan, Patrick J. ; Pérez-Herrán, Esther ; Jiménez, Elena ; Esquivias, Jorge ; Barros, David ; Ballell, Lluís ; Alemparte, Carlos ; Besra, Gurdyal S. / Inhibiting mycobacterial tryptophan synthase by targeting the inter-subunit interface. In: Scientific Reports. 2017 ; Vol. 7.
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Abrahams, KA, Cox, JAG, Fütterer, K, Rullas, J, Ortega-Muro, F, Loman, NJ, Moynihan, PJ, Pérez-Herrán, E, Jiménez, E, Esquivias, J, Barros, D, Ballell, L, Alemparte, C & Besra, GS 2017, 'Inhibiting mycobacterial tryptophan synthase by targeting the inter-subunit interface', Scientific Reports, vol. 7, 9430. https://doi.org/10.1038/s41598-017-09642-y

Inhibiting mycobacterial tryptophan synthase by targeting the inter-subunit interface. / Abrahams, Katherine A.; Cox, Jonathan A.G.; Fütterer, Klaus; Rullas, Joaquín; Ortega-Muro, Fátima; Loman, Nicholas J.; Moynihan, Patrick J.; Pérez-Herrán, Esther; Jiménez, Elena; Esquivias, Jorge; Barros, David; Ballell, Lluís; Alemparte, Carlos; Besra, Gurdyal S.

In: Scientific Reports, Vol. 7, 9430, 25.08.2017.

Research output: Contribution to journalArticle

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