Mycothiol: A promising antitubercular target

Nilewar, Shrikant; Kathiravan, Muthu K.

doi:10.1016/j.bioorg.2013.11.004

Cited by 16 publications

(10 citation statements)

References 59 publications

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“…tuberculosis (Table S3) and could represent possible future drug-targets. This would be particularly attractive in combination with inhibitors of MSH biosynthesis to combat tuberculosis (TB) disease since MshB inhibitors are successfully applied in the clinical practice 54, 55 .…”

Section: Discussionmentioning

confidence: 99%

Monitoring global protein thiol-oxidation and protein S-mycothiolation in Mycobacterium smegmatis under hypochlorite stress

Hillion

Bernhardt

Busche

et al. 2017

Sci Rep

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Mycothiol (MSH) is the major low molecular weight (LMW) thiol in Actinomycetes. Here, we used shotgun proteomics, OxICAT and RNA-seq transcriptomics to analyse protein S-mycothiolation, reversible thiol-oxidations and their impact on gene expression in Mycobacterium smegmatis under hypochlorite stress. In total, 58 S-mycothiolated proteins were identified under NaOCl stress that are involved in energy metabolism, fatty acid and mycolic acid biosynthesis, protein translation, redox regulation and detoxification. Protein S-mycothiolation was accompanied by MSH depletion in the thiol-metabolome. Quantification of the redox state of 1098 Cys residues using OxICAT revealed that 381 Cys residues (33.6%) showed >10% increased oxidations under NaOCl stress, which overlapped with 40 S-mycothiolated Cys-peptides. The absence of MSH resulted in a higher basal oxidation level of 338 Cys residues (41.1%). The RseA and RshA anti-sigma factors and the Zur and NrdR repressors were identified as NaOCl-sensitive proteins and their oxidation resulted in an up-regulation of the SigH, SigE, Zur and NrdR regulons in the RNA-seq transcriptome. In conclusion, we show here that NaOCl stress causes widespread thiol-oxidation including protein S-mycothiolation resulting in induction of antioxidant defense mechanisms in M. smegmatis. Our results further reveal that MSH is important to maintain the reduced state of protein thiols.

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Section: Discussionmentioning

confidence: 99%

Monitoring global protein thiol-oxidation and protein S-mycothiolation in Mycobacterium smegmatis under hypochlorite stress

Hillion

Bernhardt

Busche

et al. 2017

Sci Rep

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“…Thus, inhibitors of MSH biosynthesis enzymes are promising candidates for antituberculosis drug developments. Several MSH biosynthesis inhibitors have been applied that target the MSH- S -conjugate amidase Mca, the deacetylase MshB, the cysteine ligase MshC and the MSSM reductase Mtr that are attractive antituberculosis drug targets (Nilewar and Kathiravan, 2014 ).…”

Section: Biosynthesis and Functions Of Major Lmw Thiol-redox Buffers mentioning

confidence: 99%

Redox regulation by reversible protein S-thiolation in bacteria

2015

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Low molecular weight (LMW) thiols function as thiol-redox buffers to maintain the reduced state of the cytoplasm. The best studied LMW thiol is the tripeptide glutathione (GSH) present in all eukaryotes and Gram-negative bacteria. Firmicutes bacteria, including Bacillus and Staphylococcus species utilize the redox buffer bacillithiol (BSH) while Actinomycetes produce the related redox buffer mycothiol (MSH). In eukaryotes, proteins are post-translationally modified to S-glutathionylated proteins under conditions of oxidative stress. S-glutathionylation has emerged as major redox-regulatory mechanism in eukaryotes and protects active site cysteine residues against overoxidation to sulfonic acids. First studies identified S-glutathionylated proteins also in Gram-negative bacteria. Advances in mass spectrometry have further facilitated the identification of protein S-bacillithiolations and S-mycothiolation as BSH- and MSH-mixed protein disulfides formed under oxidative stress in Firmicutes and Actinomycetes, respectively. In Bacillus subtilis, protein S-bacillithiolation controls the activities of the redox-sensing OhrR repressor and the methionine synthase MetE in vivo. In Corynebacterium glutamicum, protein S-mycothiolation was more widespread and affected the functions of the maltodextrin phosphorylase MalP and thiol peroxidase (Tpx). In addition, novel bacilliredoxins (Brx) and mycoredoxins (Mrx1) were shown to function similar to glutaredoxins in the reduction of BSH- and MSH-mixed protein disulfides. Here we review the current knowledge about the functions of the bacterial thiol-redox buffers glutathione, bacillithiol, and mycothiol and the role of protein S-thiolation in redox regulation and thiol protection in model and pathogenic bacteria.

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“…In conjunction with mycothiol (MSH), MCA plays an analogous role to glutathione in eukaryotes in protecting the cell against oxidative stress by covalently binding to alkylating agents, electrophiles, and drugs to form mycothiol‐ S ‐conjugates . Therefore, it is essential for growth and survival of M. tuberculosis . MCA shares no sequence homology to other known eukaryotic enzymes and, hence, drugs inhibiting MCA homologs represent a novel and attractive target for new classes of antimycobacterials .…”

Section: Marine Invertebrate Compounds With Anti‐tb Activitymentioning

confidence: 99%

“…Therefore, it is essential for growth and survival of M. tuberculosis . MCA shares no sequence homology to other known eukaryotic enzymes and, hence, drugs inhibiting MCA homologs represent a novel and attractive target for new classes of antimycobacterials . It is assumed that the spiro‐isoxazoline and oximino amide groups of 49 and 50 , respectively, mimic conformations of mycothiol‐ S ‐conjugates, and therefore, act as substrate mimics .…”

Section: Marine Invertebrate Compounds With Anti‐tb Activitymentioning

confidence: 99%

Antimycobacterial Metabolites from Marine Invertebrates

Ancheeva

Chaidir²,

Kalscheuer

et al. 2016

Archiv der Pharmazie

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Marine organisms play an important role in natural product-based drug research due to accumulation of structurally unique and bioactive metabolites. The exploration of marine-derived compounds may significantly extend the scientific knowledge of potential scaffolds for antibiotic drug discovery. Development of novel antitubercular agents is especially significant as the emergence of drug-resistant Mycobacterium tuberculosis strains remains threateningly high. Marine invertebrates (i.e., sponges, corals, gorgonians) as a source of new chemical entities are the center of research for several scientific groups, and the wide spectrum of biological activities of marine-derived compounds encourages scientists to carry out investigations in the field of antibiotic research, including tuberculosis treatment. The present review covers published data on antitubercular natural products from marine invertebrates grouped according to their biogenetic origin. Studies on the structure-activity relationships of these important leads are highlighted as well.

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Mycothiol: A promising antitubercular target

Cited by 16 publications

References 59 publications

Monitoring global protein thiol-oxidation and protein S-mycothiolation in Mycobacterium smegmatis under hypochlorite stress

Monitoring global protein thiol-oxidation and protein S-mycothiolation in Mycobacterium smegmatis under hypochlorite stress

Redox regulation by reversible protein S-thiolation in bacteria

Antimycobacterial Metabolites from Marine Invertebrates

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