Distribution and infection-related functions of bacillithiol in Staphylococcus aureus

Pöther, Dierk-Christoph; Gierok, Philipp; Harms, Manuela; Mostertz, Jörg; Hochgräfe, Falko; Antelmann, Haike; Hamilton, Christopher; Borovok, Ilya; Lalk, Michael; Aharonowitz, Yair; Hecker, Michael

doi:10.1016/j.ijmm.2013.01.003

Cited by 42 publications

(64 citation statements)

References 66 publications

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“…Growth studies with 10 mM H 2 O 2 showed a growth delay of the fosB and bshA mutants, suggesting that both BSH and FosB may play a role in the cell's response to oxidative stress. In the study carried out by Pöther et al (14), strain 8325-4, a bshC mutant, was found to show equal resistance to 10, 20, and 40 mM H 2 O 2 as the exogenously complemented, BSH-producing isogenic strains, divergent from what we have found in this study. In that study (14), LB medium was used, while we used TSB here.…”

Section: Discussioncontrasting

confidence: 75%

“…In the study carried out by Pöther et al (14), strain 8325-4, a bshC mutant, was found to show equal resistance to 10, 20, and 40 mM H 2 O 2 as the exogenously complemented, BSH-producing isogenic strains, divergent from what we have found in this study. In that study (14), LB medium was used, while we used TSB here. Pöther et al (14) noted that LB medium can quench oxidants because of the peptides and amino acids present in the medium.…”

Section: Discussioncontrasting

confidence: 75%

“…In that study (14), LB medium was used, while we used TSB here. Pöther et al (14) noted that LB medium can quench oxidants because of the peptides and amino acids present in the medium. In addition, unpublished work done in the Cheung lab has shown that the concentration of H 2 O 2 necessary to kill S. aureus is dependent on the amount of cells present.…”

Section: Discussionmentioning

confidence: 99%

“…The addition of 500 M Cys to the culture medium did not increase the fosfomycin resistance of the bshA mutants ( Table 2). The laboratory strain SH1000 contains an intact fosB gene but does not produce BSH due to a missense mutation in the bshC coding region (13,14). Following repair of the bshC gene in SH1000 to yield strain ALC7446, increased fosfomycin resistance was seen in ALC7446 compared to that seen in isogenic strain SH1000 (625 g/ml versus 9.3 g/ml, respectively) ( Table 2).…”

Section: Fosb Utilizes Bsh As a Substrate To Confer Fosfomycin Resistmentioning

confidence: 99%

“…While multiple bshB paralogs occur in Bacillus species (11,12), there is only one, bshB2, in S. aureus (11). Interestingly, laboratory strains of S. aureus in the 8325 lineage, such as SH1000 and 8325-4, contain an 8-bp insertion in bshC which renders the protein inactive and, hence, prevents the synthesis of BSH (13,14).…”

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Importance of Bacillithiol in the Oxidative Stress Response of Staphylococcus aureus

et al. 2014

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In Staphylococcus aureus, the low-molecular-weight thiol called bacillithiol (BSH), together with cognate S-transferases, is believed to be the counterpart to the glutathione system of other organisms. To explore the physiological role of BSH in S. aureus, we constructed mutants with the deletion of bshA (sa1291), which encodes the glycosyltransferase that catalyzes the first step of BSH biosynthesis, and fosB (sa2124), which encodes a BSH-S-transferase that confers fosfomycin resistance, in several S. aureus strains, including clinical isolates. Mutation of fosB or bshA caused a 16-to 60-fold reduction in fosfomycin resistance in these S. aureus strains. High-pressure liquid chromatography analysis, which quantified thiol extracts, revealed some variability in the amounts of BSH present across S. aureus strains. Deletion of fosB led to a decrease in BSH levels. The fosB and bshA mutants of strain COL and a USA300 isolate, upon further characterization, were found to be sensitive to H 2 O 2 and exhibited decreased NADPH levels compared with those in the isogenic parents. Microarray analyses of COL and the isogenic bshA mutant revealed increased expression of genes involved in staphyloxanthin synthesis in the bshA mutant relative to that in COL under thiol stress conditions. However, the bshA mutant of COL demonstrated decreased survival compared to that of the parent in human wholeblood survival assays; likewise, the naturally BSH-deficient strain SH1000 survived less well than its BSH-producing isogenic counterpart. Thus, the survival of S. aureus under oxidative stress is facilitated by BSH, possibly via a FosB-mediated mechanism, independently of its capability to produce staphyloxanthin.

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Section: Discussioncontrasting

confidence: 75%

Section: Discussioncontrasting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Fosb Utilizes Bsh As a Substrate To Confer Fosfomycin Resistmentioning

confidence: 99%

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confidence: 99%

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Importance of Bacillithiol in the Oxidative Stress Response of Staphylococcus aureus

et al. 2014

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Oxidation of bacillithiol during killing ofStaphylococcus aureusUSA300 inside neutrophil phagosomes

Ashby

Springer

Loi

et al. 2022

Journal of Leukocyte Biology

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Targeting immune evasion tactics of pathogenic bacteria may hold the key to treating recalcitrant bacterial infections. Staphylococcus aureus produces bacillithiol (BSH), its major low‐molecular‐weight thiol, which is thought to protect this opportunistic human pathogen against the bombardment of oxidants inside neutrophil phagosomes. Here, we show that BSH was oxidized when human neutrophils phagocytosed S. aureus, but provided limited protection to the bacteria. We used mass spectrometry to measure the oxidation of BSH upon exposure of S. aureus USA300 to either a bolus of hypochlorous acid (HOCl) or a flux generated by the neutrophil enzyme myeloperoxidase. Oxidation of BSH and loss of bacterial viability were strongly correlated (r = 0.99, p < 0.001). BSH was fully oxidized after exposure of S. aureus to lethal doses of HOCl. However, there was no relationship between the initial BSH levels and the dose of HOCl required for bacterial killing. In contrast to the HOCl systems, only 50% of total BSH was oxidized when neutrophils killed the majority of phagocytosed bacteria. Oxidation of BSH was decreased upon inhibition of myeloperoxidase, implicating HOCl in phagosomal BSH oxidation. A BSH‐deficient S. aureus USA300 mutant was slightly more susceptible to treatment with either HOCl or ammonia chloramine, or to killing within neutrophil phagosomes. Collectively, our data show that myeloperoxidase‐derived oxidants react with S. aureus inside neutrophil phagosomes, leading to partial BSH oxidation, and contribute to bacterial killing. However, BSH offers only limited protection against the neutrophil's multifaceted killing mechanisms.

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Beyond Glutathione: Different Low Molecular Weight Thiols as Mediators of Redox Regulation and Other Metabolic Functions in Lower Organisms

Hamilton

Arbach

Groom³

2014

Recent Advances in Redox Active Plant and Microbial Products

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Distribution and infection-related functions of bacillithiol in Staphylococcus aureus

Cited by 42 publications

References 66 publications

Importance of Bacillithiol in the Oxidative Stress Response of Staphylococcus aureus

Importance of Bacillithiol in the Oxidative Stress Response of Staphylococcus aureus

Oxidation of bacillithiol during killing ofStaphylococcus aureusUSA300 inside neutrophil phagosomes

Beyond Glutathione: Different Low Molecular Weight Thiols as Mediators of Redox Regulation and Other Metabolic Functions in Lower Organisms

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