Catabolic Ornithine Carbamoyltransferase Activity Facilitates Growth of Staphylococcus aureus in Defined Medium Lacking Glucose and Arginine

Reslane, Itidal; Halsey, Cortney R.; Stastny, Amanda; Cabrera, Barbara J; Ahn, Jongsam; Shinde, Dhananjay; Galac, Madeline R.; Sladek, Margaret; Razvi, Fareha; Lehman, McKenzie K.; Bayles, Kenneth W.; Thomas, Vinai Chittezham; Handke, Luke D.; Fey, Paul D.

doi:10.1128/mbio.00395-22

Cited by 15 publications

(19 citation statements)

References 84 publications

(113 reference statements)

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“…These authors also showed that in the presence of glucose, and even in the absence of arginine, S. aureus behaves like an arginine auxotroph showing that absence of arginine alone is not enough to trigger arginine biosynthesis. The authors suggested that, during abscess infection, where active macrophages are found, arginine and glucose are depleted, thus activating arginine biosynthesis from proline (27). Our hypothesis is that incubation of SA at a fever-like temperature for 2 h triggers some physiological responses similar to those displayed after immune system activation even though glucose is present.…”

Section: Resultsmentioning

confidence: 99%

“…2A). Reslane et al (2022) (27) reported that when glucose and arginine are absent, SA is a functional prototroph. These authors also showed that in the presence of glucose, and even in the absence of arginine, S. aureus behaves like an arginine auxotroph showing that absence of arginine alone is not enough to trigger arginine biosynthesis.…”

Section: Metabolic Reshaping Of S Aureus and P Aeruginosa After Expos...mentioning

confidence: 99%

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Fever-like temperature impacts onStaphylococcus aureusandPseudomonas aeruginosainteraction, physiology, and virulence bothin vitroandin vivo

Venero

Galeano

Luqman

et al. 2023

Preprint

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Staphylococcus aureusandPseudomonas aeruginosaare two bacterial species that cause a wide variety of infections and coinfections. The interaction between these species is complex and involves the production of different metabolites and metabolic changes. The impact of elevated body temperature, such as fever, on the physiology and interaction of these pathogens remains poorly understood. Therefore, the aim of this work was to analyze the effect of moderate fever-like temperatures (39°C) onS. aureusUSA300 andP. aeruginosaPAO1 mono- and co-cultures in comparison with 37°C, by using RNAseq and physiological assays in microaerobiosis. Both bacterial species showed metabolic alterations in response to temperature but also in response to the competitor. Organic acid production and nitrite content in the supernatant were altered both by the presence of the competitor and the incubation temperature. Interaction ANOVA showed that, inS. aureus, gene expression presented interaction between the temperature and the presence of the competitor. Among these genes, the most relevant were theagroperon and three of its direct target genespsmβ,psmβ2andhld. In the A549 epithelial lung cell line, fever-like temperatures impacted in vitro virulence, antibiotic resistance, cell invasion, and cytokine production. In agreement with thein vitroassays, the survival of mice that had been intranasally inoculated withS. aureusmonocultures pre-incubated at 39°C showed reduced survival after 10 days. An even higher mortality of around 30% was observed in mice that had been inoculated with co-cultures pre-incubated at 39°C. The bacterial burden in the lungs, kidney, and liver was higher for both species when the mice were infected with co-cultures previously incubated at 39°C. Our results highlight a relevant change in the virulence of bacterial opportunistic pathogens exposed to fever-like temperatures, opening new questions related to bacteria-bacteria and host-pathogen interactions and coevolution.

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Section: Resultsmentioning

confidence: 99%

Section: Metabolic Reshaping Of S Aureus and P Aeruginosa After Expos...mentioning

confidence: 99%

Fever-like temperature impacts onStaphylococcus aureusandPseudomonas aeruginosainteraction, physiology, and virulence bothin vitroandin vivo

Venero

Galeano

Luqman

et al. 2023

Preprint

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“…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 (29–32). Given its requirement for arginine during planktonic growth, we hypothesized that exogenous arginine was also required for growth in a biofilm.…”

Section: Resultsmentioning

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%

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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“…While RelP and RelQ respond to stresses like cell-wall-targeting antibiotics and alterations in pH ( 10 ), Rel synthesizes (p)ppGpp during amino acid depletion, leading to large transcriptional changes, including the downregulation of protein synthesis machinery and upregulation of amino acid transport and metabolism genes ( 4 ). As S. aureus is a conditional auxotroph for a number of amino acids ( 11 , 12 ), this regulation of amino acid uptake is essential for survival in starved conditions ( 9 ). In proteobacteria, (p)ppGpp modulates changes in transcription of these genes by binding to two sites around the β′ subunit of the RNA polymerase, leading to altered expression of roughly a third of the genome ( 13 ).…”

Section: Introductionmentioning

confidence: 99%

Stringent Response-Mediated Control of GTP Homeostasis Is Required for Long-Term Viability of Staphylococcus aureus

et al. 2023

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Catabolic Ornithine Carbamoyltransferase Activity Facilitates Growth of Staphylococcus aureus in Defined Medium Lacking Glucose and Arginine

Abstract: Staphylococcus aureus can cause infection in virtually any niche of the human host, suggesting that it has significant metabolic versatility. Indeed, bioinformatic analysis suggests that it has the biosynthetic capability to synthesize all 20 amino acids.

Cited by 15 publications

References 84 publications

Fever-like temperature impacts onStaphylococcus aureusandPseudomonas aeruginosainteraction, physiology, and virulence bothin vitroandin vivo

Fever-like temperature impacts onStaphylococcus aureusandPseudomonas aeruginosainteraction, physiology, and virulence bothin vitroandin vivo

Restriction of Arginine Induces Antibiotic Tolerance inStaphylococcus aureus

Stringent Response-Mediated Control of GTP Homeostasis Is Required for Long-Term Viability of Staphylococcus aureus

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