The methylglyoxal pathway is a sink for glutathione in Salmonella experiencing oxidative stress

Kant, Sashi; Liu, Lin; Vázquez‐Torres, Andrés

doi:10.1371/journal.ppat.1011441

Cited by 4 publications

(2 citation statements)

References 35 publications

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“…Thus far, studies focusing on S. pyogenes, S. mutans, and S. sanguinis have shown gloA to be the primary modulator of MG tolerance in vitro with gloB mutants having little effect (63,84). This is in support of what was observed with L. monocytogenes, but not Salmonella where it was found that gloB was more important for Salmonella resistance to oxidative stress and killing by macrophages (64,95).…”

Section: Discussionsupporting

confidence: 62%

Identification of Glyoxalase A in Group BStreptococcusand its contribution to methylglyoxal tolerance and virulence

Akbari,

Joyce,

Spencer

et al. 2024

Preprint

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Group BStreptococcus(GBS) is a Gram-positive pathobiont that commonly colonizes the gastrointestinal and lower female genital tracts but can cause sepsis and pneumonia in newborns and is a leading cause of neonatal meningitis. Despite the resulting disease severity, the pathogenesis of GBS is not completely understood, especially during the early phases of infection. To investigate GBS factors necessary for blood stream survival, we performed a transposon (Tn) mutant screen in our bacteremia infection model using a GBSmarinertransposon mutant library previously developed by our group. We identified significantly underrepresented mutations in 628 genes that contribute to survival in the blood, including those encoding known virulence factors such as capsule, the β-hemolysin, and inorganic metal ion transport systems. Most of the underrepresented genes have not been previously characterized or studied in GBS, includinggloAandgloB,which are homologs for genes involved in methylglyoxal (MG) detoxification. MG is a byproduct of glycolysis and a highly reactive toxic aldehyde that is elevated in immune cells during infection. Here, we observed MG sensitivity across multiple GBS isolates and confirm thatgloAcontributes to MG tolerance and invasive GBS infection. We show specifically thatgloAcontributes to GBS survival in the presence of neutrophils and depleting neutrophils in mice abrogates the decreased survival and infection of thegloAmutant. The requirement of the glyoxalase pathway during GBS infection suggests that MG detoxification is important for bacterial survival during host-pathogen interactions.ImportanceA transposon-mutant screen of group BStreptococcus(GBS) in a bacteremia mouse model of infection revealed virulence factors known to be important for GBS survival such as the capsule, β-hemolysin/cytolysin, and genes involved in metal homeostasis. Many uncharacterized factors were also identified including genes that are part of the metabolic pathway that breaks down methylglyoxal (MG). The glyoxalase pathway is the most ubiquitous metabolic pathway for MG breakdown and is only a two-step process using glyoxalase A (gloA) and B (gloB) enzymes. MG is a highly reactive byproduct of glycolysis and is made my most cells. Here, we show that in GBS, the first enzyme in the glyoxalase pathway, encoded bygloA, contributes to MG resistance and blood survival. We further demonstrate that GloA contributes to GBS survival against neutrophilsin vitroandin vivoand, therefore, is an important virulence factor required for invasive infection.

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Section: Discussionsupporting

confidence: 62%

Identification of Glyoxalase A in Group BStreptococcusand its contribution to methylglyoxal tolerance and virulence

Akbari,

Joyce,

Spencer

et al. 2024

Preprint

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“…This high level of glyoxalase redundancy, particularly in Cbei and Cpas point to a possible important role of these enzymes in both organisms. Because of their strict anaerobic nature [30-31], Clostridium species are particularly susceptible to oxidative damage, which might explain the preponderance of glyoxalases (in Cbei and Cpas ), which play an important role in countering oxidative stress [32-33]. In the glyoxalase system, methylglyoxal is converted to D -lactate via S - D -lactoylgluthatione and eventually to pyruvate [29, 34].…”

Section: Discussionmentioning

confidence: 99%

Unravelling the roadblocks to 1,2-propanediol biosynthesis in select solventogenicClostridiumspecies

Agyeman-Duah,

Kumar,

Ujor

2024

Preprint

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BackgroundThe compound 1,2-propanediol is an important industrial bulk chemical that has proven particularly recalcitrant to bio-production. Solvent-producingClostridiumspecies represent promising candidates for engineering 1,2-propaediol production. Co-production of 1,2-popanediol and butanol has the potential to improve the economics of the acetone-butanol-ethanol (ABE) fermentation.ResultsIn this study, the methylglyoxal synthase gene (mgsA) fromClostridium beijerinckiiNCIMB 8052 was homologously expressed in this organism. Additionally, a separate strain ofClostridium beijerinckiiNCIMB 8052 was engineered by cloning and expressingmgsAand methylglyoxal/glyoxal reductase (mgR) fromClostridium pasteurianumATCC 6013 as a fused protein linked by polyglycine linker in the former. Both strains ofC. beijerinckiiNCIMB 8052 failed to produce 1,2-propaneol. Instead, traces of acetol—the precursor of 1,2-propanediol—were detected in cultures of both strains. When the recombinant strains were exposed to acetol, both strains exhibited ∼100% acetol-to-1,2-propanediol conversion efficiency. Conversely, methylglyoxal supplementation led to the production of traces of acetol but not lactaldehyde or 1,2-propanediol. When wildtypeC. beijerinckiiNCIMB 8052,C. pasteurianumATCC 6013 andClostridium tyrobutyricumATCC 25755 were challenged with methylglyoxal,C. beijerinckiiproduced ∼0.1 g/L (S)-(+)-1,2-Propanediol, whileC. tyrobutyricumproduced traces of lactate.C. pasteurianumproduced neither 1,2-propanediol nor lactate. The wild types of all three species above exhibited ∼100% acetol-to-1,2-propanediol conversion efficiency. The recombinant strain ofC. beijerinckiiexpressing fused MgsA and MgR fromC. pasteurianumATCC 6013 showed enhanced growth and solvent production, producing as high as 88% more butanol on both glucose and lactose than the control strain and the recombinant strain of the same organism expressing the native MgsA.ConclusionsRecombinant and native strains ofC. beijerinckii,C. pasteurianumandC. tyrobutyricumstudied in this work exhibit extremely poor capacity to catalyze the conversion of the intermediates of the methylglyoxal bypass to 1,2-propanediol. This is indicative of lack of appropriate enzymes to catalyze the reactions from methylglyoxal to acetol or lactaldehyde. Inability to detect methylglyoxal in the recombinant strains harboringmgsA(both homologous and heterologous)— whereas the strain expressing bothmgsAandmgRfromC. pasteurianum, under the same promoter (Padc) produced higher concentrations of butanol—suggests thatC. beijerinckiimight possess a regulatory mechanism that limits the activity of methylglyoxal-producing MgsA. The protein product ofmgRfromC. pasteurianumrepresents a promising metabolic engineering candidate towards increasing butanol production.

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Anaerobic respiration of host-derived methionine sulfoxide protects intracellular Salmonella from the phagocyte NADPH oxidase

Kim,

Liu,

Kant

et al. 2024

Cell Host & Microbe

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The methylglyoxal pathway is a sink for glutathione in Salmonella experiencing oxidative stress

Cited by 4 publications

References 35 publications

Identification of Glyoxalase A in Group BStreptococcusand its contribution to methylglyoxal tolerance and virulence

Identification of Glyoxalase A in Group BStreptococcusand its contribution to methylglyoxal tolerance and virulence

Unravelling the roadblocks to 1,2-propanediol biosynthesis in select solventogenicClostridiumspecies

Anaerobic respiration of host-derived methionine sulfoxide protects intracellular Salmonella from the phagocyte NADPH oxidase

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