Identification of a Mycothiol-Dependent Nitroreductase from <i>Mycobacterium tuberculosis</i>

Negri, Ana; Javidnia, Prisca Elis; Mu, Ran; Zhang, Xiaojie; Vendôme, Jérémie; Gold, Ben; Roberts, Julia; Barman, D; Ioerger, Thomas R.; Sacchettini, James C.; Jiang, Xiuju; Burns-Huang, Kristin; Warrier, Thulasi; Lv, Yan; Warren, Joel; Oren, Deena A.; Beuming, Thijs; Wang, Hongyao; Wu, Jie; Li, Haitao; Rhee, Kyu Y.; Nathan, Carl; Liu, Gang; Somersan-Karakaya, Selin

doi:10.1021/acsinfecdis.7b00111

Cited by 17 publications

(31 citation statements)

References 65 publications

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“…Importantly, NFC-resistant mutants were selected which had mutations in the gene encoding Rv2466c. This indicates that the MSH-dependent nitroreductase activity of Rv2466c is crucial for pro-drug activation [28] . Rv2466c has a DsbA-like structure and can also function as mycoredoxin-2 in demycothiolation with electrons from the MSH/Mtr pathway [30] .…”

Section: Biosynthesis and Functions Of Mycothiol And Bacillithiol In mentioning

confidence: 94%

“…MSH further contributes to antibiotic resistance in Mycobacterium tuberculosis ( Mtb ). MSH is required for activation of the pro-drugs isoniazid (INH) and nitrofuranylcalanolides (NFCs) which are potent anti-mycobacterial drugs [27] , [28] . INH is activated by the catalase KatG and MSH, leading to NAD-INH adduct formation and inhibition of the enoyl -ACP reductase (InhA) of the mycolic acid biosynthesis pathway [29] .…”

Section: Biosynthesis and Functions Of Mycothiol And Bacillithiol In mentioning

confidence: 99%

“…INH resistant Mtb isolates often carry spontaneous mutations in katG or mshA [14] . Novel antimycobacterial drugs, such as the nitrofurantoin derivatives NFC or the thienopyrimidine compound TP053 are activated by the MSH-dependent oxidoreductase Rv2466c, which was recently revealed as MSH-dependent nitroreductase to reduce nitro groups to amines [28] , [30] . Importantly, NFC-resistant mutants were selected which had mutations in the gene encoding Rv2466c.…”

Section: Biosynthesis and Functions Of Mycothiol And Bacillithiol In mentioning

confidence: 99%

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Redox regulation by reversible protein S-thiolation in Gram-positive bacteria

2019

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Low molecular weight (LMW) thiols play an important role as thiol-cofactors for many enzymes and are crucial to maintain the reduced state of the cytoplasm. Most Gram-negative bacteria utilize glutathione (GSH) as major LMW thiol. However, in Gram-positive Actinomycetes and Firmicutes alternative LMW thiols, such as mycothiol (MSH) and bacillithiol (BSH) play related roles as GSH surrogates, respectively. Under conditions of hypochlorite stress, MSH and BSH are known to form mixed disulfides with protein thiols, termed as S-mycothiolation or S-bacillithiolation that function in thiol-protection and redox regulation. Protein S-thiolations are widespread redox-modifications discovered in different Gram-positive bacteria, such as Bacillus and Staphylococcus species, Mycobacterium smegmatis, Corynebacterium glutamicum and Corynebacterium diphtheriae. S-thiolated proteins are mainly involved in cellular metabolism, protein translation, redox regulation and antioxidant functions with some conserved targets across bacteria. The reduction of protein S-mycothiolations and S-bacillithiolations requires glutaredoxin-related mycoredoxin and bacilliredoxin pathways to regenerate protein functions.In this review, we present an overview of the functions of mycothiol and bacillithiol and their physiological roles in protein S-bacillithiolations and S-mycothiolations in Gram-positive bacteria. Significant progress has been made to characterize the role of protein S-thiolation in redox-regulation and thiol protection of main metabolic and antioxidant enzymes. However, the physiological roles of the pathways for regeneration are only beginning to emerge as well as their interactions with other cellular redox systems. Future studies should be also directed to explore the roles of protein S-thiolations and their redox pathways in pathogenic bacteria under infection conditions to discover new drug targets and treatment options against multiple antibiotic resistant bacteria.

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Section: Biosynthesis and Functions Of Mycothiol And Bacillithiol In mentioning

confidence: 94%

Section: Biosynthesis and Functions Of Mycothiol And Bacillithiol In mentioning

confidence: 99%

Section: Biosynthesis and Functions Of Mycothiol And Bacillithiol In mentioning

confidence: 99%

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Redox regulation by reversible protein S-thiolation in Gram-positive bacteria

2019

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“…A novel MSH-dependent reductase (Rv2466c) involved in the activation of the pro-drug TP052, a thieno-pyrimidine derivative able to kill Mtb , was found to be essential for bacterial survival during exposure to H 2 O 2 (Newton et al, 2011; Albesa-Jové et al, 2014; Rosado et al, 2017). Recently, it was shown that Rv2466c functions as a noncanonical nitroreductase that relies on MSH for the reduction of nitro-containing compounds (Negri et al, 2018). Under oxidative stress conditions, Mtb increases (via sigma H, E, and B) the expression of thioredoxin reductase/thioredoxin together with enzymes involved in MSH synthesis (Raman et al, 2001; Newton and Fahey, 2008).…”

Section: Pathogen Virulence and Antioxidant Networkmentioning

confidence: 99%

Reactive species and pathogen antioxidant networks during phagocytosis

Piacenza

Trujillo

Radí

2019

Journal of Experimental Medicine

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The generation of phagosomal cytotoxic reactive species (i.e., free radicals and oxidants) by activated macrophages and neutrophils is a crucial process for the control of intracellular pathogens. The chemical nature of these species, the reactions they are involved in, and the subsequent effects are multifaceted and depend on several host- and pathogen-derived factors that influence their production rates and catabolism inside the phagosome. Pathogens rely on an intricate and synergistic antioxidant armamentarium that ensures their own survival by detoxifying reactive species. In this review, we discuss the generation, kinetics, and toxicity of reactive species generated in phagocytes, with a focus on the response of macrophages to internalized pathogens and concentrating on Mycobacterium tuberculosis and Trypanosoma cruzi as examples of bacterial and parasitic infection, respectively. The ability of pathogens to deal with host-derived reactive species largely depends on the competence of their antioxidant networks at the onset of invasion, which in turn can tilt the balance toward pathogen survival, proliferation, and virulence over redox-dependent control of infection.

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“…For example, we have recently demonstrated that the intracellular pathogen R. equi carries genes encoding three mycoredoxins with overlapping roles during host cell infection, being necessary at least one of them for intracellular survival [70]. This is important, because their partially overlapping roles may explain why other authors had not observed any attenuation in mutant strains carrying deletions on just one of the mycoredoxins present in the genome of other actinobacterial pathogens, such as M. tuberculosis [75]. Overall, the structure of the Brx and Mrx redoxins is well conserved among different bacterial species [67,70,76], which may explain their overlapping roles in maintaining the redox homeostasis of different intracellular pathogens.…”

Section: Enzymatic Reparation Mechanisms Of Protein Oxidationmentioning

confidence: 99%

Oxidative Stress-Generating Antimicrobials, a Novel Strategy to Overcome Antibacterial Resistance

et al. 2020

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Antimicrobial resistance is becoming one of the most important human health issues. Accordingly, the research focused on finding new antibiotherapeutic strategies is again becoming a priority for governments and major funding bodies. The development of treatments based on the generation of oxidative stress with the aim to disrupt the redox defenses of bacterial pathogens is an important strategy that has gained interest in recent years. This approach is allowing the identification of antimicrobials with repurposing potential that could be part of combinatorial chemotherapies designed to treat infections caused by recalcitrant bacterial pathogens. In addition, there have been important advances in the identification of novel plant and bacterial secondary metabolites that may generate oxidative stress as part of their antibacterial mechanism of action. Here, we revised the current status of this emerging field, focusing in particular on novel oxidative stress-generating compounds with the potential to treat infections caused by intracellular bacterial pathogens.

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Identification of a Mycothiol-Dependent Nitroreductase from Mycobacterium tuberculosis

Cited by 17 publications

References 65 publications

Redox regulation by reversible protein S-thiolation in Gram-positive bacteria

Redox regulation by reversible protein S-thiolation in Gram-positive bacteria

Reactive species and pathogen antioxidant networks during phagocytosis

Oxidative Stress-Generating Antimicrobials, a Novel Strategy to Overcome Antibacterial Resistance

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