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Review 2: "Restriction of Arginine Induces Antibiotic Tolerance in Staphylococcus Aureus"

Reviewers find the study well-designed, with experiments showing arginine depletion causes antibiotic tolerance in Staphylococcus aureus by inhibiting protein synthesis, though prior connections between arginine and tolerance exist.

Published onNov 28, 2023
Review 2: "Restriction of Arginine Induces Antibiotic Tolerance in Staphylococcus Aureus"
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Restriction of Arginine Induces Antibiotic Tolerance in Staphylococcus aureus
Restriction of Arginine Induces Antibiotic Tolerance in Staphylococcus aureus

Abstract 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, particularly when they are caused by Methicillin-Resistant Staphylococcus 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. aureus biofilms 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 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 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, although S. aureus fitness in a mouse skin infection model is decreased in an argH mutant, its ability to survive in vivo during antibiotic treatment with vancomycin is enhanced, 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.Significance Statement Methicillin-Resistant Staphylococcus aureus (MRSA) is a leading bacterial cause of morbidity and mortality worldwide. Despite the availability of numerous antibiotics with in vitro efficacy against MRSA, there are still high rates of antibiotic treatment failure in S. aureus infections, suggesting antibiotic tolerance is common during human infections. Here, we report a direct connection between the metabolism of arginine, an essential amino acid in S. aureus, and tolerance to multiple classes of antibiotics. This represents a key pathway towards broad antibiotic tolerance in S. aureus and therefore an attractive target to help repotentiate current antibiotics and potentially reduce treatment failure.

RR:C19 Evidence Scale rating by reviewer:

  • Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.



Staphylococcus arginine auxotrophy promotes broad antibiotic tolerance via inhibition of protein biosynthesis under conditions where arginine is limiting. Intriguingly, this results in a double-edged sword where the inability to synthesize arginine is associated with reduced colonization, yet increased tolerance in a skin infection model. 

The manuscript by Freiberg et al reports a series of experiments that aim to assess genetic determinants of antibiotic tolerance in Staphylococcus aureus, an important pathogen in which antibiotic treatment failure due to development of antibiotic tolerance is a critical threat. The authors discover that multidrug tolerance depends on arginine homeostasis. When S. aureus is subjected to starvation for essential amino acids (most prominently arginine), tolerance is induced through reduction in protein biogenesis. This was observed both in vitro and in vivo in a mouse model for S. aureus skin infection.

The study is well-designed and exhibits a logical flow. The experiments are well-controlled and the conclusions supported by data. In particular, the chemical genetics data are very elegant and convincing: The authors show that arginine depletion increases tolerance, which can be reversed by the addition of citrulline (which can be converted to arginine by S. aureus), but only in the presence of the enzyme catalyzing this conversion, argH. It is not entirely clear, however, why arginine takes a special place. The data in Fig. 2 C show that other essential amino acids (E, H and W) are also depleted from biofilms; however, this is not discussed in the manuscript. 

While the findings are not entirely novel (both inhibition of protein synthesis in general, and the contribution of arginine in particular have been noted before), this study none the less opens up intriguing possibilities for future therapy. 

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