Bactericidal Disruption of Magnesium Metallostasis in Mycobacterium tuberculosis Is Counteracted by Mutations in the Metal Ion Transporter CorA

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 bacilli exhibiting phenotypic tolerance to most antibiotics in the standard treatment regimen. Confounding...

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Published in:	mBio Vol. 10; no. 4
Main Authors:	Lopez Quezada, Landys, Silve, Sandra, Kelinske, Mark, Liba, Amir, Diaz Gonzalez, Constantino, Kotev, Martin, Goullieux, Laurent, Sans, Stephanie, Roubert, Christine, Lagrange, Sophie, Bacqué, Eric, Couturier, Cedric, Pellet, Alain, Blanc, Isabelle, Ferron, Marlène, Debu, Fabrice, Li, Kelin, Aubé, Jeffrey, Roberts, Julia, Little, David, Ling, Yan, Zhang, Jun, Gold, Ben, Nathan, Carl
Format:	Journal Article
Language:	English
Published:	United States American Society for Microbiology 09-07-2019
Subjects:	Antitubercular Agents - pharmacology Cation Transport Proteins - genetics CorA DNA Replication Homeostasis magnesium Magnesium - metabolism Molecular Biology and Physiology Mutation mycobacterium Mycobacterium tuberculosis - drug effects Mycobacterium tuberculosis - genetics tuberculosis magnesium mycobacterium CorA tuberculosis
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Summary:	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 bacilli exhibiting phenotypic tolerance to most antibiotics in the standard treatment regimen. Confounding this problem is the increasing incidence of heritable multidrug-resistant 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 Both families of compounds depleted of intrabacterial magnesium. Complete or partial resistance to both chemotypes arose from mutations in the putative mycobacterial Mg /Co ion channel, CorA. Excess extracellular Mg , but not other divalent cations, diminished the compounds' cidality against replicating These findings establish depletion of intrabacterial magnesium as an antimicrobial mechanism of action and show that magnesium homeostasis is vulnerable to disruption by structurally diverse, nonchelating, drug-like compounds. Antimycobacterial agents might shorten the course of treatment by reducing the number of phenotypically tolerant bacteria if they could kill in diverse metabolic states. Here we report two chemically disparate classes of agents that kill 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 Mg /Co transporter, conferred resistance to the compounds when was under replicating conditions but not under nonreplicating conditions, illustrating that a given compound can kill in different metabolic states by disparate mechanisms. Targeting magnesium metallostasis represents a previously undescribed antimycobacterial mode of action that might cripple in a Mg -deficient intraphagosomal environment of macrophages.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2161-2129 2150-7511
DOI:	10.1128/mBio.01405-19