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Review 1: "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 1: "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
Description

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:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review: 

The types of nutrients available to bacterial pathogens can effect how easy they are to eradicate with antibiotic therapies. Arginine restriction induces antibiotic tolerance in Staphylococcus aureus.

Antibiotic tolerance, a phenomenon whereby bacteria can survive in the presence of otherwise active antibiotics, has been increasingly implicated in persistent clinical infections. In this study, focusing on biofilms in particular, Freiberg et al. link arginine restriction and disruptions in arginine biosynthesis to antibiotic tolerance in Staphylococcus aureus.

In the first part of the study, the authors performed screens using LFQ proteomics and TnSeq to assess the effects of antibiotic exposure on artificially grown biofilms. Cross-referencing the results of these orthogonal approaches identified coordinated responses in arginine metabolism suggesting that decreased arginine is associated with increased fitness under antibiotic stress. Next, through amino acid profiling of biofilms using HPLC, they identify that arginine is absent from biofilms and conclude its necessity as a growth-limiting factor. In the second part of the study, the authors demonstrate arginine deprivation results in multi-drug tolerance in both biofilms and planktonic culture and link the mechanism to a disruption in protein translation. Importantly, they further recapitulate the tolerant phenotype using several methods that disrupt protein translation. Overall, the manuscript provides convincing evidence that arginine plays an important role in protein translation, and that when protein translation is inhibited, either by lack of arginine or through other chemical means, a tolerant phenotype develops. 

However, we do have some comments:

In summary, the authors present convincing data that arginine restriction, or more generally, protein translation inhibition, conveys antibiotic tolerance. Although this is consistent with the currently accepted model and mechanism of multi-drug antibiotic tolerance, the specific link between arginine deprivation and tolerance presented here is new. 

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