Staphylococcus aureus Does Not Synthesize Arginine from Proline under Physiological Conditions

Jeong, Bohyun; Shah, Majid Ali; Roh, Eunjung; Kim, Kyeongkyu; Park, Indal; Bae, Taeok

doi:10.1128/jb.00018-22

Cited by 4 publications

(4 citation statements)

References 35 publications

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“…Among the enzymes in the arginine synthesis pathway, only ArgG and ArgH were found at levels above the limit of detection in our proteomic dataset. ArgD, ArgC, ArgJ, and ArgB were not found, consistent with other work showing these enzymes are under high levels of transcriptional repression (30)(31)(32)56). S. aureus contains multiple enzymatic pathways that catabolize arginine, which helps create an environment that can rapidly consume any exogenous arginine, thus limiting the availability of arginine for protein synthesis.…”

Section: Discussionsupporting

confidence: 89%

“…Since arginine metabolism was implicated as having a role in antibiotic tolerance in both screens, we sought to better understand the role of arginine within S. aureus biofilms. S. aureus is unique in that it contains intact copies of the genes encoding all of the enzymes necessary to synthesize arginine from glutamate or proline, but is auxotrophic for arginine during planktonic growth (29)(30)(31)(32).…”

Section: Antibiotic Exposure Results In Differences In Protein Abunda...mentioning

confidence: 99%

“…The ability of S. aureus to induce tolerance by restricting its own arginine synthesis pathway may explain a long-standing paradox-namely that wildtype S. aureus has fully functional arginine synthesis enzymes yet does not synthesize arginine under any in vitro conditions that have been tested thus far (31, 32). In line with other studies, S. aureus was unable to grow without arginine (Figure 2).…”

Section: Discussionmentioning

confidence: 99%

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Restriction of Arginine Induces Antibiotic Tolerance inStaphylococcus aureus

Freiberg,

Ruiz,

Green

et al. 2023

Preprint

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Staphylococcus aureusis responsible for a substantial number of invasive infections globally each year. These infections are problematic because they are frequently recalcitrant to antibiotic treatment, particularly when they are caused by Methicillin-ResistantStaphylococcus aureus(MRSA). Antibiotic tolerance, the ability for bacteria to persist despite normally lethal doses of antibiotics, is responsible for most antibiotic treatment failure in MRSA infections. To understand how antibiotic tolerance is induced,S. aureusbiofilms exposed to multiple anti-MRSA antibiotics (vancomycin, ceftaroline, delafloxacin, and linezolid) were examined using both quantitative proteomics and transposon sequencing. These screens indicated that arginine metabolism is involved in antibiotic tolerance within a biofilm and led to the hypothesis that depletion of arginine withinS. aureuscommunities can induce antibiotic tolerance. Consistent with this hypothesis, inactivation ofargH,the final gene in the arginine synthesis pathway, induces antibiotic tolerance under conditions in which the parental strain is susceptible to antibiotics. Arginine restriction was found to induce antibiotic tolerance via inhibition of protein synthesis. Finally, althoughS. aureusfitness in a mouse skin infection model is decreased in anargHmutant, its ability to survivein vivoduring antibiotic treatment with vancomycin is enhanced, highlighting the relationship between arginine metabolism and antibiotic tolerance duringS. aureusinfection. Uncovering this link between arginine metabolism and antibiotic tolerance has the potential to open new therapeutic avenues targeting previously recalcitrantS. aureusinfections.Significance StatementMethicillin-ResistantStaphylococcus aureus(MRSA) is a leading bacterial cause of morbidity and mortality worldwide. Despite the availability of numerous antibiotics within vitroefficacy against MRSA, there are still high rates of antibiotic treatment failure inS. aureusinfections, suggesting antibiotic tolerance is common during human infections. Here, we report a direct connection between the metabolism of arginine, an essential amino acid inS. aureus, and tolerance to multiple classes of antibiotics. This represents a key pathway towards broad antibiotic tolerance inS. aureusand therefore an attractive target to help repotentiate current antibiotics and potentially reduce treatment failure.

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Section: Discussionsupporting

confidence: 89%

Section: Antibiotic Exposure Results In Differences In Protein Abunda...mentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Restriction of Arginine Induces Antibiotic Tolerance inStaphylococcus aureus

Freiberg,

Ruiz,

Green

et al. 2023

Preprint

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“…In agreement with the higher seed protein content reported for M92-220 (2012CM7F040p05ar154bMN15), there is an increased abundance of these two amino acids in the MT seeds. It is unlikely that the increased abundance of arginine resulted from the proline biosynthetic pathway suggested by some other investigations (Jeong et al, 2022;Tomlinson et al, 2011) because there was a concomitant increase in abundance of glutamic acid.…”

Section: Crop Sciencementioning

confidence: 90%

Non‐targeted metabolite profiling of a fast neutron soybean mutant reveals an increase in sulfur‐containing metabolites

Islam,

Krishnan,

Slovin

et al. 2024

Crop Science

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Soybean [Glycine max (L.) Merr] seed is a valuable source of raw materials of protein, oil, and metabolites for food, feed, and pharmaceutical industries. Using global metabolic profiling, we identified 718 non‐redundant metabolites of a fast neutron‐mediated soybean known to have 24 genes deleted and 15% more seed protein compared to wild‐type seed. Among the 554 identified metabolites in leaves and 629 identified in seed, 465 were found in both leaves and seed. Mapping of the deleted genes and identified metabolites indicated a complex perturbation of global metabolism involving glutamine‐arginine, aspartate, aromatic amino acid, glycolytic, and tricarboxylic acid cycle (TCA) pathways. The mutant seed showed a higher content of sulfur‐containing metabolites such as S‐methylmethionine, methionine, and cysteine compared to wild‐type seed. The gene deletions may alter carbon flow from glycolytic and TCA pathways, resulting in higher protein content and increased abundance of sulfur‐containing metabolites in the mutant seeds. The results provide valuable information for altering metabolic pathways to increase value‐added seed traits in soybeans.

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Restriction of arginine induces antibiotic tolerance in Staphylococcus aureus

Freiberg,

Reyes Ruiz,

Gimza

et al. 2024

Nat Commun

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Staphylococcus aureus is responsible for a substantial number of invasive infections globally each year. These infections are problematic because they are frequently recalcitrant to antibiotic treatment. Antibiotic tolerance, the ability of bacteria to persist despite normally lethal doses of antibiotics, contributes to antibiotic treatment failure in S. aureus infections. To understand how antibiotic tolerance is induced, S. aureus biofilms exposed to multiple anti-staphylococcal antibiotics are examined using both quantitative proteomics and transposon sequencing. These screens indicate that arginine metabolism is involved in antibiotic tolerance within a biofilm and support the hypothesis that depletion of arginine within S. aureus communities can induce antibiotic tolerance. Consistent with this hypothesis, inactivation of argH , the final gene in the arginine synthesis pathway, induces antibiotic tolerance. Arginine restriction induces antibiotic tolerance via inhibition of protein synthesis. In murine skin and bone infection models, an argH mutant has enhanced ability to survive antibiotic treatment with vancomycin, highlighting the relationship between arginine metabolism and antibiotic tolerance during S. aureus infection. Uncovering this link between arginine metabolism and antibiotic tolerance has the potential to open new therapeutic avenues targeting previously recalcitrant S. aureus infections.

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Staphylococcus aureus Does Not Synthesize Arginine from Proline under Physiological Conditions

Cited by 4 publications

References 35 publications

Restriction of Arginine Induces Antibiotic Tolerance inStaphylococcus aureus

Restriction of Arginine Induces Antibiotic Tolerance inStaphylococcus aureus

Non‐targeted metabolite profiling of a fast neutron soybean mutant reveals an increase in sulfur‐containing metabolites

Restriction of arginine induces antibiotic tolerance in Staphylococcus aureus

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