Identification of 4-Amino-Thieno[2,3-<italic toggle="yes">d</italic>]Pyrimidines as QcrB Inhibitors in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>

ABSTRACT Antibiotic resistance is a global crisis that threatens our ability to treat bacterial infections, such as tuberculosis, caused by Mycobacterium tuberculosis. Of the 10 million cases of tuberculosis in 2017, approximately 19% of new cases and 43% of previously treated cases were caused by s...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Gregory A. Harrison, Anne E. Mayer Bridwell, Megh Singh, Keshav Jayaraman, Leslie A. Weiss, Rachel L. Kinsella, Janessa S. Aneke, Kelly Flentie, Miranda E. Schene, Margaret Gaggioli, Samantha D. Solomon, Scott A. Wildman, Marvin J. Meyers, Christina L. Stallings
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	CydAB Mycobacterium tuberculosis QcrB antibiotic cytochrome drug discovery Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/ad17de60be774608b65761e5e9fd4004
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:ad17de60be774608b65761e5e9fd4004
record_format	dspace
spelling	oai:doaj.org-article:ad17de60be774608b65761e5e9fd40042021-11-15T15:27:33ZIdentification of 4-Amino-Thieno[2,3-<italic toggle="yes">d</italic>]Pyrimidines as QcrB Inhibitors in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>10.1128/mSphere.00606-192379-5042https://doaj.org/article/ad17de60be774608b65761e5e9fd40042019-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00606-19https://doaj.org/toc/2379-5042ABSTRACT Antibiotic resistance is a global crisis that threatens our ability to treat bacterial infections, such as tuberculosis, caused by Mycobacterium tuberculosis. Of the 10 million cases of tuberculosis in 2017, approximately 19% of new cases and 43% of previously treated cases were caused by strains of M. tuberculosis resistant to at least one frontline antibiotic. There is a clear need for new therapies that target these genetically resistant strains. Here, we report the discovery of a new series of antimycobacterial compounds, 4-amino-thieno[2,3-d]pyrimidines, that potently inhibit the growth of M. tuberculosis. To elucidate the mechanism by which these compounds inhibit M. tuberculosis, we selected for mutants resistant to a representative 4-amino-thieno[2,3-d]pyrimidine and sequenced these strains to identify the mutations that confer resistance. We isolated a total of 12 resistant mutants, each of which harbored a nonsynonymous mutation in the gene qcrB, which encodes a subunit of the electron transport chain (ETC) enzyme cytochrome bc1 oxidoreductase, leading us to hypothesize that 4-amino-thieno[2,3-d]pyrimidines target this enzyme complex. We found that addition of 4-amino-thieno[2,3-d]pyrimidines to M. tuberculosis cultures resulted in a decrease in ATP levels, supporting our model that these compounds inhibit the M. tuberculosis ETC. Furthermore, 4-amino-thieno[2,3-d]pyrimidines had enhanced activity against a mutant of M. tuberculosis deficient in cytochrome bd oxidase, which is a hallmark of cytochrome bc1 inhibitors. Therefore, 4-amino-thieno[2,3-d]pyrimidines represent a novel series of QcrB inhibitors that build on the growing number of chemical scaffolds that are able to inhibit the mycobacterial cytochrome bc1 complex. IMPORTANCE The global tuberculosis (TB) epidemic has been exacerbated by the rise in drug-resistant TB cases worldwide. To tackle this crisis, it is necessary to identify new vulnerable drug targets in Mycobacterium tuberculosis, the causative agent of TB, and develop compounds that can inhibit the bacterium through novel mechanisms of action. The QcrB subunit of the electron transport chain enzyme cytochrome bc1 has recently been validated to be a potential drug target. In the current work, we report the discovery of a new class of QcrB inhibitors, 4-amino-thieno[2,3-d]pyrimidines, that potently inhibit M. tuberculosis growth in vitro. These compounds are chemically distinct from previously reported QcrB inhibitors, and therefore, 4-amino-thieno[2,3-d]pyrimidines represent a new scaffold that can be exploited to inhibit this drug target.Gregory A. HarrisonAnne E. Mayer BridwellMegh SinghKeshav JayaramanLeslie A. WeissRachel L. KinsellaJanessa S. AnekeKelly FlentieMiranda E. ScheneMargaret GaggioliSamantha D. SolomonScott A. WildmanMarvin J. MeyersChristina L. StallingsAmerican Society for MicrobiologyarticleCydABMycobacterium tuberculosisQcrBantibioticcytochromedrug discoveryMicrobiologyQR1-502ENmSphere, Vol 4, Iss 5 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	CydAB Mycobacterium tuberculosis QcrB antibiotic cytochrome drug discovery Microbiology QR1-502
spellingShingle	CydAB Mycobacterium tuberculosis QcrB antibiotic cytochrome drug discovery Microbiology QR1-502 Gregory A. Harrison Anne E. Mayer Bridwell Megh Singh Keshav Jayaraman Leslie A. Weiss Rachel L. Kinsella Janessa S. Aneke Kelly Flentie Miranda E. Schene Margaret Gaggioli Samantha D. Solomon Scott A. Wildman Marvin J. Meyers Christina L. Stallings Identification of 4-Amino-Thieno[2,3-<italic toggle="yes">d</italic>]Pyrimidines as QcrB Inhibitors in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
description	ABSTRACT Antibiotic resistance is a global crisis that threatens our ability to treat bacterial infections, such as tuberculosis, caused by Mycobacterium tuberculosis. Of the 10 million cases of tuberculosis in 2017, approximately 19% of new cases and 43% of previously treated cases were caused by strains of M. tuberculosis resistant to at least one frontline antibiotic. There is a clear need for new therapies that target these genetically resistant strains. Here, we report the discovery of a new series of antimycobacterial compounds, 4-amino-thieno[2,3-d]pyrimidines, that potently inhibit the growth of M. tuberculosis. To elucidate the mechanism by which these compounds inhibit M. tuberculosis, we selected for mutants resistant to a representative 4-amino-thieno[2,3-d]pyrimidine and sequenced these strains to identify the mutations that confer resistance. We isolated a total of 12 resistant mutants, each of which harbored a nonsynonymous mutation in the gene qcrB, which encodes a subunit of the electron transport chain (ETC) enzyme cytochrome bc1 oxidoreductase, leading us to hypothesize that 4-amino-thieno[2,3-d]pyrimidines target this enzyme complex. We found that addition of 4-amino-thieno[2,3-d]pyrimidines to M. tuberculosis cultures resulted in a decrease in ATP levels, supporting our model that these compounds inhibit the M. tuberculosis ETC. Furthermore, 4-amino-thieno[2,3-d]pyrimidines had enhanced activity against a mutant of M. tuberculosis deficient in cytochrome bd oxidase, which is a hallmark of cytochrome bc1 inhibitors. Therefore, 4-amino-thieno[2,3-d]pyrimidines represent a novel series of QcrB inhibitors that build on the growing number of chemical scaffolds that are able to inhibit the mycobacterial cytochrome bc1 complex. IMPORTANCE The global tuberculosis (TB) epidemic has been exacerbated by the rise in drug-resistant TB cases worldwide. To tackle this crisis, it is necessary to identify new vulnerable drug targets in Mycobacterium tuberculosis, the causative agent of TB, and develop compounds that can inhibit the bacterium through novel mechanisms of action. The QcrB subunit of the electron transport chain enzyme cytochrome bc1 has recently been validated to be a potential drug target. In the current work, we report the discovery of a new class of QcrB inhibitors, 4-amino-thieno[2,3-d]pyrimidines, that potently inhibit M. tuberculosis growth in vitro. These compounds are chemically distinct from previously reported QcrB inhibitors, and therefore, 4-amino-thieno[2,3-d]pyrimidines represent a new scaffold that can be exploited to inhibit this drug target.
format	article
author	Gregory A. Harrison Anne E. Mayer Bridwell Megh Singh Keshav Jayaraman Leslie A. Weiss Rachel L. Kinsella Janessa S. Aneke Kelly Flentie Miranda E. Schene Margaret Gaggioli Samantha D. Solomon Scott A. Wildman Marvin J. Meyers Christina L. Stallings
author_facet	Gregory A. Harrison Anne E. Mayer Bridwell Megh Singh Keshav Jayaraman Leslie A. Weiss Rachel L. Kinsella Janessa S. Aneke Kelly Flentie Miranda E. Schene Margaret Gaggioli Samantha D. Solomon Scott A. Wildman Marvin J. Meyers Christina L. Stallings
author_sort	Gregory A. Harrison
title	Identification of 4-Amino-Thieno[2,3-<italic toggle="yes">d</italic>]Pyrimidines as QcrB Inhibitors in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_short	Identification of 4-Amino-Thieno[2,3-<italic toggle="yes">d</italic>]Pyrimidines as QcrB Inhibitors in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_full	Identification of 4-Amino-Thieno[2,3-<italic toggle="yes">d</italic>]Pyrimidines as QcrB Inhibitors in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_fullStr	Identification of 4-Amino-Thieno[2,3-<italic toggle="yes">d</italic>]Pyrimidines as QcrB Inhibitors in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_full_unstemmed	Identification of 4-Amino-Thieno[2,3-<italic toggle="yes">d</italic>]Pyrimidines as QcrB Inhibitors in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
title_sort	identification of 4-amino-thieno[2,3-<italic toggle="yes">d</italic>]pyrimidines as qcrb inhibitors in <named-content content-type="genus-species">mycobacterium tuberculosis</named-content>
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/ad17de60be774608b65761e5e9fd4004
work_keys_str_mv	AT gregoryaharrison identificationof4aminothieno23italictoggleyesditalicpyrimidinesasqcrbinhibitorsinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontent AT anneemayerbridwell identificationof4aminothieno23italictoggleyesditalicpyrimidinesasqcrbinhibitorsinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontent AT meghsingh identificationof4aminothieno23italictoggleyesditalicpyrimidinesasqcrbinhibitorsinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontent AT keshavjayaraman identificationof4aminothieno23italictoggleyesditalicpyrimidinesasqcrbinhibitorsinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontent AT leslieaweiss identificationof4aminothieno23italictoggleyesditalicpyrimidinesasqcrbinhibitorsinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontent AT rachellkinsella identificationof4aminothieno23italictoggleyesditalicpyrimidinesasqcrbinhibitorsinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontent AT janessasaneke identificationof4aminothieno23italictoggleyesditalicpyrimidinesasqcrbinhibitorsinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontent AT kellyflentie identificationof4aminothieno23italictoggleyesditalicpyrimidinesasqcrbinhibitorsinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontent AT mirandaeschene identificationof4aminothieno23italictoggleyesditalicpyrimidinesasqcrbinhibitorsinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontent AT margaretgaggioli identificationof4aminothieno23italictoggleyesditalicpyrimidinesasqcrbinhibitorsinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontent AT samanthadsolomon identificationof4aminothieno23italictoggleyesditalicpyrimidinesasqcrbinhibitorsinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontent AT scottawildman identificationof4aminothieno23italictoggleyesditalicpyrimidinesasqcrbinhibitorsinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontent AT marvinjmeyers identificationof4aminothieno23italictoggleyesditalicpyrimidinesasqcrbinhibitorsinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontent AT christinalstallings identificationof4aminothieno23italictoggleyesditalicpyrimidinesasqcrbinhibitorsinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontent
_version_	1718427970972942336

Identification of 4-Amino-Thieno[2,3-<italic toggle="yes">d</italic>]Pyrimidines as QcrB Inhibitors in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>

Ejemplares similares