Open AccessBactericidal Disruption of Magnesium Metallostasis in Mycobacterium tuberculosis Is Counteracted by Mutations in the Metal Ion Transporter CorA
Author(s) -
Landys Lopez Quezada,
Sandra Silve,
Mark Kelinske,
Amir Liba,
Constantino Diaz Gonzalez,
Martin Kotev,
Laurent Goullieux,
Stéphanie Sans,
Christine Roubert,
Sophie Lagrange,
Eric Bacqué,
Cédric Couturier,
Alain Pellet,
Isabelle Blanc,
Marlène Ferron,
Fabrice Debu,
Kelin Li,
Jeffrey Aubé,
Julia Roberts,
David Little,
Yan Lv,
Jun Zhang,
Ben Gold,
Carl Nathan
Publication year - 2019
Publication title -
mbio
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.562
H-Index - 121
eISSN - 2161-2129
pISSN - 2150-7511
DOI - 10.1128/mbio.01405-19
Subject(s) - antimycobacterial , mycobacterium tuberculosis , tuberculosis , magnesium , chemistry , mode of action , microbiology and biotechnology , transporter , bacteria , mechanism of action , biology , biochemistry , gene , genetics , medicine , in vitro , organic chemistry , pathology
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 Mg 2+ /Co 2+ ion channel, CorA. Excess extracellular Mg 2+ , 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 Mg 2+ /Co 2+ 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 Mg 2+ -deficient intraphagosomal environment of macrophages.