Abstract
BackgroundThree low molecular weight thiols are synthesized by Mycobacterium tuberculosis (M.tb), namely ergothioneine (ERG), mycothiol (MSH) and gamma-glutamylcysteine (GGC). They are able to counteract reactive oxygen species (ROS) and/or reactive nitrogen species (RNS). In addition, the production of ERG is elevated in the MSH-deficient M.tb mutant, while the production of MSH is elevated in the ERG-deficient mutants. Furthermore, the production of GGC is elevated in the MSH-deficient mutant and the ERG-deficient mutants. The propensity of one thiol to be elevated in the absence of the other prompted further investigations into their interplay in M.tb.MethodsTo achieve that, we generated two M.tb mutants that are unable to produce ERG nor MSH but are able to produce a moderate (ΔegtD-mshA) or significantly high (ΔegtB-mshA) amount of GGC relative to the wild-type strain. In addition, we generated an M.tb mutant that is unable to produce GGC nor MSH but is able to produce a significantly low level of ERG (ΔegtA-mshA) relative to the wild-type strain. The susceptibilities of these mutants to various in vitro and ex vivo stress conditions were investigated and compared.ResultsThe ΔegtA-mshA mutant was the most susceptible to cellular stress relative to its parent single mutant strains (ΔegtA and ∆mshA) and the other double mutants. In addition, it displayed a growth-defect in vitro, in mouse and human macrophages suggesting; that the complete inhibition of ERG, MSH and GGC biosynthesis is deleterious for the growth of M.tb.ConclusionsThis study indicates that ERG, MSH and GGC are able to compensate for each other to maximize the protection and ensure the fitness of M.tb. This study therefore suggests that the most effective strategy to target thiol biosynthesis for anti-tuberculosis drug development would be the simultaneous inhibition of the biosynthesis of ERG, MSH and GGC.
Highlights
Three low molecular weight thiols are synthesized by Mycobacterium tuberculosis (M.tb), namely ergothioneine (ERG), mycothiol (MSH) and gamma-glutamylcysteine (GGC)
All double mutant had a growth defect in media supplemented with ADS or Oleic acid (OADC) relative to the wild-type strain (Fig. 2a and b)
The growth defect of the ΔegtA-mshA mutant relative to its parent strains is more pronounced in the media supplemented with ADS (Fig. 2c) relative to media supplemented with OADC (Fig. 2d)
Summary
Three low molecular weight thiols are synthesized by Mycobacterium tuberculosis (M.tb), namely ergothioneine (ERG), mycothiol (MSH) and gamma-glutamylcysteine (GGC) They are able to counteract reactive oxygen species (ROS) and/or reactive nitrogen species (RNS). The host susceptibility to TB depends largely on its ability to fight invading mycobacteria by generating reactive oxygen species (ROS) and reactive nitrogen species (RNS) [3] This became evident when the NADPH oxidase deficient (NOX2) mice and iNOS (inducible nitric oxide synthase) deficient mice were found to be more susceptible to TB infection than the wild-type mice [4, 5]. Previous studies suggest a role of the phagocyte NADPH oxidase in the release of cytokines, implicating an interplay between the production of cytokines and the production of ROS, though the mechanism remains ambiguous This interplay may be implicated in the structural organization and formation of granuloma [7]
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