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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2019-08-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.01405-19 |
| _version_ | 1818822475328258048 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-18T23:24:40Z |
| format | Article |
| id | doaj.art-36d78fae9ed74d22a77a85998cdfb018 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-18T23:24:40Z |
| publishDate | 2019-08-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-36d78fae9ed74d22a77a85998cdfb0182022-12-21T20:47:50ZengAmerican Society for MicrobiologymBio2150-75112019-08-0110410.1128/mBio.01405-19Bactericidal Disruption of Magnesium Metallostasis in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Is Counteracted by Mutations in the Metal Ion Transporter CorALandys Lopez Quezada0Sandra Silve1Mark Kelinske2Amir Liba3Constantino Diaz Gonzalez4Martin Kotev5Laurent Goullieux6Stephanie Sans7Christine Roubert8Sophie Lagrange9Eric Bacqué10Cedric Couturier11Alain Pellet12Isabelle Blanc13Marlène Ferron14Fabrice Debu15Kelin Li16Jeffrey Aubé17Julia Roberts18David Little19Yan Ling20Jun Zhang21Ben Gold22Carl Nathan23Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York, USAEvotec Infectious Diseases (Lyon), Marcy l’Etoile, FranceAgilent Technologies, Inc., Wilmington, Delaware, USAAgilent Technologies, Inc., Wilmington, Delaware, USAEvotec Research Informatics (Toulouse), Toulouse, FranceEvotec Research Informatics (Toulouse), Toulouse, FranceEvotec Infectious Diseases (Lyon), Marcy l’Etoile, FranceEvotec Infectious Diseases (Lyon), Marcy l’Etoile, FranceEvotec Infectious Diseases (Lyon), Marcy l’Etoile, FranceEvotec Infectious Diseases (Lyon), Marcy l’Etoile, FranceEvotec Infectious Diseases (Lyon), Marcy l’Etoile, FranceEvotec Infectious Diseases (Lyon), Marcy l’Etoile, FranceEvotec Infectious Diseases (Lyon), Marcy l’Etoile, FranceEvotec Infectious Diseases (Lyon), Marcy l’Etoile, FranceEvotec Infectious Diseases (Lyon), Marcy l’Etoile, FranceEvotec Infectious Diseases (Lyon), Marcy l’Etoile, FranceDivision of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USADivision of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USADepartment of Microbiology and Immunology, Weill Cornell Medicine, New York, New York, USADepartment of Microbiology and Immunology, Weill Cornell Medicine, New York, New York, USADepartment of Microbiology and Immunology, Weill Cornell Medicine, New York, New York, USADepartment of Microbiology and Immunology, Weill Cornell Medicine, New York, New York, USADepartment of Microbiology and Immunology, Weill Cornell Medicine, New York, New York, USADepartment of Microbiology and Immunology, Weill Cornell Medicine, New York, New York, USAABSTRACT 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.https://journals.asm.org/doi/10.1128/mBio.01405-19CorAmagnesiummycobacteriumtuberculosis |
| spellingShingle | 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 mBio CorA magnesium mycobacterium tuberculosis |
| 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_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_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_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 |
| topic | CorA magnesium mycobacterium tuberculosis |
| url | https://journals.asm.org/doi/10.1128/mBio.01405-19 |
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