Skip to main content
SearchLoginLogin or Signup

Review 1: "The Spx Stress Regulator Confers High-level β-lactam Resistance and Decreases Susceptibility to Last-line Antibiotics in Methicillin Resistant Staphylococcus Aureus"

The reviewers found the study compelling, clearly demonstrating the role of the YjbH-Spx pathway in modulating β-lactam resistance and susceptibility to other cell wall targeting antibiotics in MRSA.

Published onApr 26, 2024
Review 1: "The Spx Stress Regulator Confers High-level β-lactam Resistance and Decreases Susceptibility to Last-line Antibiotics in Methicillin Resistant Staphylococcus Aureus"
1 of 2
key-enterThis Pub is a Review of
The Spx stress regulator confers high-level β-lactam resistance and decreases susceptibility to last-line antibiotics in methicillin resistant Staphylococcus aureus
The Spx stress regulator confers high-level β-lactam resistance and decreases susceptibility to last-line antibiotics in methicillin resistant Staphylococcus aureus
Description

Abstract Infections caused by methicillin resistant Staphylococcus aureus (MRSA) are a leading cause of mortality worldwide. MRSA have acquired resistance to next generation β-lactam antibiotics through the horizontal acquisition of the mecA resistance gene. Development of high resistance is, however, often associated with additional mutations in a set of chromosomal core genes, known as potentiators which through poorly described mechanisms enhance resistance. The yjbH gene was recently identified as a hot spot for adaptive mutations during severe infections. Here, we show that inactivation of yjbH increased β-lactam MICs up to 16-folds and transformed MRSA cells with low level of resistance to being homogenously highly resistant to β-lactams. The yjbH gene encodes an adaptor protein that targets the transcriptional stress regulator Spx for degradation by the ClpXP protease. Using CRISPRi to knock down spx transcription, we unambiguously linked hyper-resistance to accumulation of Spx. Spx was previously proposed to be essential, however, our data indicate that Spx is dispensable for growth at 37°C but becomes essential in the presence of antibiotics with various targets. On the other hand, high Spx levels bypassed the role of PBP4 in β-lactam resistance and broadly decreased MRSA susceptibility to compounds targeting the cell wall or the cell membrane including vancomycin, daptomycin, and nisin. Strikingly, Spx potentiated resistance independently of its redox sensing switch. Collectively, our study identifies a general stress pathway that, in addition to promoting the development of high-level, broad-spectrum β-lactam resistance, also decreases MRSA susceptibility to critical antibiotics of last resort.

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.

***************************************

Review: The manuscript by Nielsen et. al. present interesting results. Authors has shown that the inactivation of yjbH gene enhances the β-lactam MICs in MRSA strains. Suggestions are as follows:

  1. Line # 24- 25; This sentence needs to rephrase in better way for the clarity e.g. “high level of resistance’’ not high resistance.

  2. Figure 3 is confusing to me; authors has shown slight increase in daptomycin or vancomycin MIC.

  3. Based on the current data of daptomycin susceptibility (probably spot assay) did not support the change in daptomycin susceptibility, it’s very moderate change or negligible. 

  4. I would suggest authors to test the daptomycin and vancomycin MICs by microbroth dilution method of yjbH mutant vs JE2 WT strain to add the data in the Table 1.

  5. In addition, if the daptomycin MIC changes significantly then only authors should discuss the relevance of daptomycin in the manuscript. Otherwise, it would exaggerate the message and mislead the readers.

  6. Based on the above suggestions, authors may require modifying the title bit. Now combination therapies are getting popular so authors should avoid over emphasis of the “last line of the antibiotics”. 

  7. I would suggest rechecking the overall grammar and syntax of the manuscript.

Comments
0
comment
No comments here
Why not start the discussion?