Restriction of Arginine Induces Antibiotic Tolerance in Staphylococcus aureus

  1. Jeffrey A. Freiberg
  2. Valeria M. Reyes Ruiz
  3. Erin R. Green
  4. Eric P. Skaar

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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.

Article activity feed

  1. PREreview

    This Zenodo record is a permanently preserved version of a Structured PREreview. You can view the complete PREreview at https://prereview.org/reviews/10393658.

    Does the introduction explain the objective of the research presented in the preprint? Yes Yes, it clearly states that the objective of the research is to address the high mortality rate associated with Staphylococcus aureus infections, particularly those that fail to respond to antibiotics.
    Are the methods well-suited for this research? Highly appropriate They use a combination of different methods to allow for multifaceted exploration, which is then integrated with proteomics and sequencing data to enhance reliability.
    Are the conclusions supported by the data? Highly supported Each conclusions is paired with a comprehensive interpretation based on the experimental data and analyses performed.
    Are the data presentations, including visualizations, well-suited to represent the data? I don't know
    How clearly do the authors discuss, explain, and interpret their findings and potential next steps for the research? Very clearly They clearly describe experimental data, highlight results, and create connections between cellular mechanism in relation to antibiotic resistant in S. aureus. Furthermore, they describe any potential limitations of the study as well as provide a variety of potential avenues for further study of the information found.
    Is the preprint likely to advance academic knowledge? Highly likely It offers key insights into the bacterial mechanisms that are increasingly presenting as a threat to human health.
    Would it benefit from language editing? No
    Would you recommend this preprint to others? Yes, it's of high quality
    Is it ready for attention from an editor, publisher or broader audience? Yes, as it is

    Competing interests

    The author declares that they have no competing interests.

  2. PREreview

    This Zenodo record is a permanently preserved version of a Structured PREreview. You can view the complete PREreview at https://prereview.org/reviews/10275873.

    Does the introduction explain the objective of the research presented in the preprint? Yes
    Are the methods well-suited for this research? Highly appropriate
    Are the conclusions supported by the data? Highly supported
    Are the data presentations, including visualizations, well-suited to represent the data? Highly appropriate and clear
    How clearly do the authors discuss, explain, and interpret their findings and potential next steps for the research? Very clearly
    Is the preprint likely to advance academic knowledge? Highly likely
    Would it benefit from language editing? No
    Would you recommend this preprint to others? Yes, it's of high quality
    Is it ready for attention from an editor, publisher or broader audience? Yes, as it is

    Competing interests

    The author declares that they have no competing interests.

  3. Rapid Reviews Infectious Diseases

    Tobias Dörr

    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.

  4. Rapid Reviews Infectious Diseases

    Matthew Culyba, Edwin Chen

    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.

  6. Version published to 10.1101/2023.10.12.561972v1 on bioRxiv