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
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
Affiliations
Landys Lopez Quezada
Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York, USA
Sandra Silve
Evotec Infectious Diseases (Lyon), Marcy l’Etoile, France
Mark Kelinske
Agilent Technologies, Inc., Wilmington, Delaware, USA
Amir Liba
Agilent Technologies, Inc., Wilmington, Delaware, USA
Constantino Diaz Gonzalez
Evotec Research Informatics (Toulouse), Toulouse, France
Martin Kotev
Evotec Research Informatics (Toulouse), Toulouse, France
Laurent Goullieux
Evotec Infectious Diseases (Lyon), Marcy l’Etoile, France
Stephanie Sans
Evotec Infectious Diseases (Lyon), Marcy l’Etoile, France
Christine Roubert
Evotec Infectious Diseases (Lyon), Marcy l’Etoile, France
Sophie Lagrange
Evotec Infectious Diseases (Lyon), Marcy l’Etoile, France
Eric Bacqué
Evotec Infectious Diseases (Lyon), Marcy l’Etoile, France
Cedric Couturier
Evotec Infectious Diseases (Lyon), Marcy l’Etoile, France
Alain Pellet
Evotec Infectious Diseases (Lyon), Marcy l’Etoile, France
Isabelle Blanc
Evotec Infectious Diseases (Lyon), Marcy l’Etoile, France
Marlène Ferron
Evotec Infectious Diseases (Lyon), Marcy l’Etoile, France
Fabrice Debu
Evotec Infectious Diseases (Lyon), Marcy l’Etoile, France
Kelin Li
Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Jeffrey Aubé
Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Julia Roberts
Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York, USA
David Little
Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York, USA
Yan Ling
Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York, USA
Jun Zhang
Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York, USA
Ben Gold
Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York, USA
Carl Nathan
Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York, USA
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.