Bactericidal Disruption of Magnesium Metallostasis in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Is Counteracted by Mutations in the Metal Ion Transporter CorA

ABSTRACT A defining characteristic of treating tuberculosis is the need for prolonged administration of multiple drugs. This may be due in part to subpopulations of slowly replicating or nonreplicating Mycobacterium tuberculosis bacilli exhibiting phenotypic tolerance to most antibiotics in the stan...

Descripción completa

Guardado en:
Detalles Bibliográficos
Autores principales: Landys Lopez Quezada, Sandra Silve, Mark Kelinske, Amir Liba, Constantino Diaz Gonzalez, Martin Kotev, Laurent Goullieux, Stephanie Sans, Christine Roubert, Sophie Lagrange, Eric Bacqué, Cedric Couturier, Alain Pellet, Isabelle Blanc, Marlène Ferron, Fabrice Debu, Kelin Li, Jeffrey Aubé, Julia Roberts, David Little, Yan Ling, Jun Zhang, Ben Gold, Carl Nathan
Formato: article
Lenguaje:EN
Publicado: American Society for Microbiology 2019
Materias:
Acceso en línea:https://doaj.org/article/36d78fae9ed74d22a77a85998cdfb018
Etiquetas: Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
id oai:doaj.org-article:36d78fae9ed74d22a77a85998cdfb018
record_format dspace
spelling oai:doaj.org-article:36d78fae9ed74d22a77a85998cdfb0182021-11-15T16:22:11ZBactericidal Disruption of Magnesium Metallostasis in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Is Counteracted by Mutations in the Metal Ion Transporter CorA10.1128/mBio.01405-192150-7511https://doaj.org/article/36d78fae9ed74d22a77a85998cdfb0182019-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01405-19https://doaj.org/toc/2150-7511ABSTRACT A defining characteristic of treating tuberculosis is the need for prolonged administration of multiple drugs. This may be due in part to subpopulations of slowly replicating or nonreplicating Mycobacterium tuberculosis bacilli exhibiting phenotypic tolerance to most antibiotics in the standard treatment regimen. Confounding this problem is the increasing incidence of heritable multidrug-resistant M. tuberculosis. A search for new antimycobacterial chemical scaffolds that can kill phenotypically drug-tolerant mycobacteria uncovered tricyclic 4-hydroxyquinolines and a barbituric acid derivative with mycobactericidal activity against both replicating and nonreplicating M. tuberculosis. Both families of compounds depleted M. tuberculosis of intrabacterial magnesium. Complete or partial resistance to both chemotypes arose from mutations in the putative mycobacterial Mg2+/Co2+ ion channel, CorA. Excess extracellular Mg2+, but not other divalent cations, diminished the compounds’ cidality against replicating M. tuberculosis. These findings establish depletion of intrabacterial magnesium as an antimicrobial mechanism of action and show that M. tuberculosis magnesium homeostasis is vulnerable to disruption by structurally diverse, nonchelating, drug-like compounds. IMPORTANCE Antimycobacterial agents might shorten the course of treatment by reducing the number of phenotypically tolerant bacteria if they could kill M. tuberculosis in diverse metabolic states. Here we report two chemically disparate classes of agents that kill M. tuberculosis both when it is replicating and when it is not. Under replicating conditions, the tricyclic 4-hydroxyquinolines and a barbituric acid analogue deplete intrabacterial magnesium as a mechanism of action, and for both compounds, mutations in CorA, a putative Mg2+/Co2+ transporter, conferred resistance to the compounds when M. tuberculosis was under replicating conditions but not under nonreplicating conditions, illustrating that a given compound can kill M. tuberculosis in different metabolic states by disparate mechanisms. Targeting magnesium metallostasis represents a previously undescribed antimycobacterial mode of action that might cripple M. tuberculosis in a Mg2+-deficient intraphagosomal environment of macrophages.Landys Lopez QuezadaSandra SilveMark KelinskeAmir LibaConstantino Diaz GonzalezMartin KotevLaurent GoullieuxStephanie SansChristine RoubertSophie LagrangeEric BacquéCedric CouturierAlain PelletIsabelle BlancMarlène FerronFabrice DebuKelin LiJeffrey AubéJulia RobertsDavid LittleYan LingJun ZhangBen GoldCarl NathanAmerican Society for MicrobiologyarticleCorAmagnesiummycobacteriumtuberculosisMicrobiologyQR1-502ENmBio, Vol 10, Iss 4 (2019)
institution DOAJ
collection DOAJ
language EN
topic CorA
magnesium
mycobacterium
tuberculosis
Microbiology
QR1-502
spellingShingle CorA
magnesium
mycobacterium
tuberculosis
Microbiology
QR1-502
Landys Lopez Quezada
Sandra Silve
Mark Kelinske
Amir Liba
Constantino Diaz Gonzalez
Martin Kotev
Laurent Goullieux
Stephanie Sans
Christine Roubert
Sophie Lagrange
Eric Bacqué
Cedric Couturier
Alain Pellet
Isabelle Blanc
Marlène Ferron
Fabrice Debu
Kelin Li
Jeffrey Aubé
Julia Roberts
David Little
Yan Ling
Jun Zhang
Ben Gold
Carl Nathan
Bactericidal Disruption of Magnesium Metallostasis in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Is Counteracted by Mutations in the Metal Ion Transporter CorA
description ABSTRACT A defining characteristic of treating tuberculosis is the need for prolonged administration of multiple drugs. This may be due in part to subpopulations of slowly replicating or nonreplicating Mycobacterium tuberculosis bacilli exhibiting phenotypic tolerance to most antibiotics in the standard treatment regimen. Confounding this problem is the increasing incidence of heritable multidrug-resistant M. tuberculosis. A search for new antimycobacterial chemical scaffolds that can kill phenotypically drug-tolerant mycobacteria uncovered tricyclic 4-hydroxyquinolines and a barbituric acid derivative with mycobactericidal activity against both replicating and nonreplicating M. tuberculosis. Both families of compounds depleted M. tuberculosis of intrabacterial magnesium. Complete or partial resistance to both chemotypes arose from mutations in the putative mycobacterial Mg2+/Co2+ ion channel, CorA. Excess extracellular Mg2+, but not other divalent cations, diminished the compounds’ cidality against replicating M. tuberculosis. These findings establish depletion of intrabacterial magnesium as an antimicrobial mechanism of action and show that M. tuberculosis magnesium homeostasis is vulnerable to disruption by structurally diverse, nonchelating, drug-like compounds. IMPORTANCE Antimycobacterial agents might shorten the course of treatment by reducing the number of phenotypically tolerant bacteria if they could kill M. tuberculosis in diverse metabolic states. Here we report two chemically disparate classes of agents that kill M. tuberculosis both when it is replicating and when it is not. Under replicating conditions, the tricyclic 4-hydroxyquinolines and a barbituric acid analogue deplete intrabacterial magnesium as a mechanism of action, and for both compounds, mutations in CorA, a putative Mg2+/Co2+ transporter, conferred resistance to the compounds when M. tuberculosis was under replicating conditions but not under nonreplicating conditions, illustrating that a given compound can kill M. tuberculosis in different metabolic states by disparate mechanisms. Targeting magnesium metallostasis represents a previously undescribed antimycobacterial mode of action that might cripple M. tuberculosis in a Mg2+-deficient intraphagosomal environment of macrophages.
format article
author Landys Lopez Quezada
Sandra Silve
Mark Kelinske
Amir Liba
Constantino Diaz Gonzalez
Martin Kotev
Laurent Goullieux
Stephanie Sans
Christine Roubert
Sophie Lagrange
Eric Bacqué
Cedric Couturier
Alain Pellet
Isabelle Blanc
Marlène Ferron
Fabrice Debu
Kelin Li
Jeffrey Aubé
Julia Roberts
David Little
Yan Ling
Jun Zhang
Ben Gold
Carl Nathan
author_facet Landys Lopez Quezada
Sandra Silve
Mark Kelinske
Amir Liba
Constantino Diaz Gonzalez
Martin Kotev
Laurent Goullieux
Stephanie Sans
Christine Roubert
Sophie Lagrange
Eric Bacqué
Cedric Couturier
Alain Pellet
Isabelle Blanc
Marlène Ferron
Fabrice Debu
Kelin Li
Jeffrey Aubé
Julia Roberts
David Little
Yan Ling
Jun Zhang
Ben Gold
Carl Nathan
author_sort Landys Lopez Quezada
title Bactericidal Disruption of Magnesium Metallostasis in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Is Counteracted by Mutations in the Metal Ion Transporter CorA
title_short Bactericidal Disruption of Magnesium Metallostasis in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Is Counteracted by Mutations in the Metal Ion Transporter CorA
title_full Bactericidal Disruption of Magnesium Metallostasis in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Is Counteracted by Mutations in the Metal Ion Transporter CorA
title_fullStr Bactericidal Disruption of Magnesium Metallostasis in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Is Counteracted by Mutations in the Metal Ion Transporter CorA
title_full_unstemmed Bactericidal Disruption of Magnesium Metallostasis in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Is Counteracted by Mutations in the Metal Ion Transporter CorA
title_sort bactericidal disruption of magnesium metallostasis in <named-content content-type="genus-species">mycobacterium tuberculosis</named-content> is counteracted by mutations in the metal ion transporter cora
publisher American Society for Microbiology
publishDate 2019
url https://doaj.org/article/36d78fae9ed74d22a77a85998cdfb018
work_keys_str_mv AT landyslopezquezada bactericidaldisruptionofmagnesiummetallostasisinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentiscounteractedbymutationsinthemetaliontransportercora
AT sandrasilve bactericidaldisruptionofmagnesiummetallostasisinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentiscounteractedbymutationsinthemetaliontransportercora
AT markkelinske bactericidaldisruptionofmagnesiummetallostasisinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentiscounteractedbymutationsinthemetaliontransportercora
AT amirliba bactericidaldisruptionofmagnesiummetallostasisinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentiscounteractedbymutationsinthemetaliontransportercora
AT constantinodiazgonzalez bactericidaldisruptionofmagnesiummetallostasisinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentiscounteractedbymutationsinthemetaliontransportercora
AT martinkotev bactericidaldisruptionofmagnesiummetallostasisinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentiscounteractedbymutationsinthemetaliontransportercora
AT laurentgoullieux bactericidaldisruptionofmagnesiummetallostasisinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentiscounteractedbymutationsinthemetaliontransportercora
AT stephaniesans bactericidaldisruptionofmagnesiummetallostasisinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentiscounteractedbymutationsinthemetaliontransportercora
AT christineroubert bactericidaldisruptionofmagnesiummetallostasisinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentiscounteractedbymutationsinthemetaliontransportercora
AT sophielagrange bactericidaldisruptionofmagnesiummetallostasisinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentiscounteractedbymutationsinthemetaliontransportercora
AT ericbacque bactericidaldisruptionofmagnesiummetallostasisinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentiscounteractedbymutationsinthemetaliontransportercora
AT cedriccouturier bactericidaldisruptionofmagnesiummetallostasisinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentiscounteractedbymutationsinthemetaliontransportercora
AT alainpellet bactericidaldisruptionofmagnesiummetallostasisinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentiscounteractedbymutationsinthemetaliontransportercora
AT isabelleblanc bactericidaldisruptionofmagnesiummetallostasisinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentiscounteractedbymutationsinthemetaliontransportercora
AT marleneferron bactericidaldisruptionofmagnesiummetallostasisinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentiscounteractedbymutationsinthemetaliontransportercora
AT fabricedebu bactericidaldisruptionofmagnesiummetallostasisinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentiscounteractedbymutationsinthemetaliontransportercora
AT kelinli bactericidaldisruptionofmagnesiummetallostasisinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentiscounteractedbymutationsinthemetaliontransportercora
AT jeffreyaube bactericidaldisruptionofmagnesiummetallostasisinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentiscounteractedbymutationsinthemetaliontransportercora
AT juliaroberts bactericidaldisruptionofmagnesiummetallostasisinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentiscounteractedbymutationsinthemetaliontransportercora
AT davidlittle bactericidaldisruptionofmagnesiummetallostasisinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentiscounteractedbymutationsinthemetaliontransportercora
AT yanling bactericidaldisruptionofmagnesiummetallostasisinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentiscounteractedbymutationsinthemetaliontransportercora
AT junzhang bactericidaldisruptionofmagnesiummetallostasisinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentiscounteractedbymutationsinthemetaliontransportercora
AT bengold bactericidaldisruptionofmagnesiummetallostasisinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentiscounteractedbymutationsinthemetaliontransportercora
AT carlnathan bactericidaldisruptionofmagnesiummetallostasisinnamedcontentcontenttypegenusspeciesmycobacteriumtuberculosisnamedcontentiscounteractedbymutationsinthemetaliontransportercora
_version_ 1718426896423714816