Synergistic Lethality of a Binary Inhibitor of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> KasA

ABSTRACT We report GSK3011724A (DG167) as a binary inhibitor of β-ketoacyl-ACP synthase (KasA) in Mycobacterium tuberculosis. Genetic and biochemical studies established KasA as the primary target. The X-ray crystal structure of the KasA-DG167 complex refined to 2.0-Å resolution revealed two interac...

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Autores principales:	Pradeep Kumar, Glenn C. Capodagli, Divya Awasthi, Riju Shrestha, Karishma Maharaja, Paridhi Sukheja, Shao-Gang Li, Daigo Inoyama, Matthew Zimmerman, Hsin Pin Ho Liang, Jansy Sarathy, Marizel Mina, George Rasic, Riccardo Russo, Alexander L. Perryman, Todd Richmann, Aditi Gupta, Eric Singleton, Sheetal Verma, Seema Husain, Patricia Soteropoulos, Zhe Wang, Roxanne Morris, Gene Porter, Gautam Agnihotri, Padmini Salgame, Sean Ekins, Kyu Y. Rhee, Nancy Connell, Véronique Dartois, Matthew B. Neiditch, Joel S. Freundlich, David Alland
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	antitubercular DG167 KasA Mycobacterium tuberculosis mycolic acid biosynthesis drug development Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/8d6c465583e4410c8afdd48c4a9a3287
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spelling	oai:doaj.org-article:8d6c465583e4410c8afdd48c4a9a32872021-11-15T15:52:19ZSynergistic Lethality of a Binary Inhibitor of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> KasA10.1128/mBio.02101-172150-7511https://doaj.org/article/8d6c465583e4410c8afdd48c4a9a32872018-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02101-17https://doaj.org/toc/2150-7511ABSTRACT We report GSK3011724A (DG167) as a binary inhibitor of β-ketoacyl-ACP synthase (KasA) in Mycobacterium tuberculosis. Genetic and biochemical studies established KasA as the primary target. The X-ray crystal structure of the KasA-DG167 complex refined to 2.0-Å resolution revealed two interacting DG167 molecules occupying nonidentical sites in the substrate-binding channel of KasA. The binding affinities of KasA to DG167 and its analog, 5g, which binds only once in the substrate-binding channel, were determined, along with the KasA-5g X-ray crystal structure. DG167 strongly augmented the in vitro activity of isoniazid (INH), leading to synergistic lethality, and also synergized in an acute mouse model of M. tuberculosis infection. Synergistic lethality correlated with a unique transcriptional signature, including upregulation of oxidoreductases and downregulation of molecular chaperones. The lead structure-activity relationships (SAR), pharmacokinetic profile, and detailed interactions with the KasA protein that we describe may be applied to evolve a next-generation therapeutic strategy for tuberculosis (TB). IMPORTANCE Cell wall biosynthesis inhibitors have proven highly effective for treating tuberculosis (TB). We discovered and validated members of the indazole sulfonamide class of small molecules as inhibitors of Mycobacterium tuberculosis KasA—a key component for biosynthesis of the mycolic acid layer of the bacterium’s cell wall and the same pathway as that inhibited by the first-line antitubercular drug isoniazid (INH). One lead compound, DG167, demonstrated synergistic lethality in combination with INH and a transcriptional pattern consistent with bactericidality and loss of persisters. Our results also detail a novel dual-binding mechanism for this compound as well as substantial structure-activity relationships (SAR) that may help in lead optimization activities. Together, these results suggest that KasA inhibition, specifically, that shown by the DG167 series, may be developed into a potent therapy that can synergize with existing antituberculars.Pradeep KumarGlenn C. CapodagliDivya AwasthiRiju ShresthaKarishma MaharajaParidhi SukhejaShao-Gang LiDaigo InoyamaMatthew ZimmermanHsin Pin Ho LiangJansy SarathyMarizel MinaGeorge RasicRiccardo RussoAlexander L. PerrymanTodd RichmannAditi GuptaEric SingletonSheetal VermaSeema HusainPatricia SoteropoulosZhe WangRoxanne MorrisGene PorterGautam AgnihotriPadmini SalgameSean EkinsKyu Y. RheeNancy ConnellVéronique DartoisMatthew B. NeiditchJoel S. FreundlichDavid AllandAmerican Society for MicrobiologyarticleantitubercularDG167KasAMycobacterium tuberculosismycolic acid biosynthesisdrug developmentMicrobiologyQR1-502ENmBio, Vol 9, Iss 6 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	antitubercular DG167 KasA Mycobacterium tuberculosis mycolic acid biosynthesis drug development Microbiology QR1-502
spellingShingle	antitubercular DG167 KasA Mycobacterium tuberculosis mycolic acid biosynthesis drug development Microbiology QR1-502 Pradeep Kumar Glenn C. Capodagli Divya Awasthi Riju Shrestha Karishma Maharaja Paridhi Sukheja Shao-Gang Li Daigo Inoyama Matthew Zimmerman Hsin Pin Ho Liang Jansy Sarathy Marizel Mina George Rasic Riccardo Russo Alexander L. Perryman Todd Richmann Aditi Gupta Eric Singleton Sheetal Verma Seema Husain Patricia Soteropoulos Zhe Wang Roxanne Morris Gene Porter Gautam Agnihotri Padmini Salgame Sean Ekins Kyu Y. Rhee Nancy Connell Véronique Dartois Matthew B. Neiditch Joel S. Freundlich David Alland Synergistic Lethality of a Binary Inhibitor of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> KasA
description	ABSTRACT We report GSK3011724A (DG167) as a binary inhibitor of β-ketoacyl-ACP synthase (KasA) in Mycobacterium tuberculosis. Genetic and biochemical studies established KasA as the primary target. The X-ray crystal structure of the KasA-DG167 complex refined to 2.0-Å resolution revealed two interacting DG167 molecules occupying nonidentical sites in the substrate-binding channel of KasA. The binding affinities of KasA to DG167 and its analog, 5g, which binds only once in the substrate-binding channel, were determined, along with the KasA-5g X-ray crystal structure. DG167 strongly augmented the in vitro activity of isoniazid (INH), leading to synergistic lethality, and also synergized in an acute mouse model of M. tuberculosis infection. Synergistic lethality correlated with a unique transcriptional signature, including upregulation of oxidoreductases and downregulation of molecular chaperones. The lead structure-activity relationships (SAR), pharmacokinetic profile, and detailed interactions with the KasA protein that we describe may be applied to evolve a next-generation therapeutic strategy for tuberculosis (TB). IMPORTANCE Cell wall biosynthesis inhibitors have proven highly effective for treating tuberculosis (TB). We discovered and validated members of the indazole sulfonamide class of small molecules as inhibitors of Mycobacterium tuberculosis KasA—a key component for biosynthesis of the mycolic acid layer of the bacterium’s cell wall and the same pathway as that inhibited by the first-line antitubercular drug isoniazid (INH). One lead compound, DG167, demonstrated synergistic lethality in combination with INH and a transcriptional pattern consistent with bactericidality and loss of persisters. Our results also detail a novel dual-binding mechanism for this compound as well as substantial structure-activity relationships (SAR) that may help in lead optimization activities. Together, these results suggest that KasA inhibition, specifically, that shown by the DG167 series, may be developed into a potent therapy that can synergize with existing antituberculars.
format	article
author	Pradeep Kumar Glenn C. Capodagli Divya Awasthi Riju Shrestha Karishma Maharaja Paridhi Sukheja Shao-Gang Li Daigo Inoyama Matthew Zimmerman Hsin Pin Ho Liang Jansy Sarathy Marizel Mina George Rasic Riccardo Russo Alexander L. Perryman Todd Richmann Aditi Gupta Eric Singleton Sheetal Verma Seema Husain Patricia Soteropoulos Zhe Wang Roxanne Morris Gene Porter Gautam Agnihotri Padmini Salgame Sean Ekins Kyu Y. Rhee Nancy Connell Véronique Dartois Matthew B. Neiditch Joel S. Freundlich David Alland
author_facet	Pradeep Kumar Glenn C. Capodagli Divya Awasthi Riju Shrestha Karishma Maharaja Paridhi Sukheja Shao-Gang Li Daigo Inoyama Matthew Zimmerman Hsin Pin Ho Liang Jansy Sarathy Marizel Mina George Rasic Riccardo Russo Alexander L. Perryman Todd Richmann Aditi Gupta Eric Singleton Sheetal Verma Seema Husain Patricia Soteropoulos Zhe Wang Roxanne Morris Gene Porter Gautam Agnihotri Padmini Salgame Sean Ekins Kyu Y. Rhee Nancy Connell Véronique Dartois Matthew B. Neiditch Joel S. Freundlich David Alland
author_sort	Pradeep Kumar
title	Synergistic Lethality of a Binary Inhibitor of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> KasA
title_short	Synergistic Lethality of a Binary Inhibitor of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> KasA
title_full	Synergistic Lethality of a Binary Inhibitor of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> KasA
title_fullStr	Synergistic Lethality of a Binary Inhibitor of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> KasA
title_full_unstemmed	Synergistic Lethality of a Binary Inhibitor of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> KasA
title_sort	synergistic lethality of a binary inhibitor of <named-content content-type="genus-species">mycobacterium tuberculosis</named-content> kasa
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/8d6c465583e4410c8afdd48c4a9a3287
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Synergistic Lethality of a Binary Inhibitor of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> KasA

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