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Review 2: "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 2: "The Spx Stress Regulator Confers High-level β-lactam Resistance and Decreases Susceptibility to Last-line Antibiotics in Methicillin Resistant Staphylococcus Aureus"
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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:

  • 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.

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Review: The authors clearly show that the molecular pathway involving YjbH adaptor protein and Spx are new elements that can alter B-lactam resistance profiles. More specifically, they show that Spx accumulation renders bacteria hyper-resistant to B-lactams and decreases MRSA susceptibitiliy to other cell-wall targeting antibiotics.

This article is a very interesting, nicely written with experiments answering all hypothesis. The authors described a very interesting observation: Hyper-resistance to B-lactam antibiotics can be observed by deletion of an adaptor protein used by a bacterial protease to degrade the transcriptional activator Spx. They clearly show that the expected accumulation of Spx due to mutation of the adaptor protein YjbH increases B-lactam but also affects resistance to other cell-wall acting antibiotics.

The most interesting observation is that this increased resistance to B-lactams is not due to changes in PBP2A or PBP4 protein levels. Resistance is achieved by modulation of other factors. Here they show that accumulation of Spx regulator is playing an essential rôle and that the redox motif of Spx is not involved in the antibiotic resistance phenotype. 

Small Comments :

  • It would be nice to see the same effects on a non-mecA background strain. Is also Spx accumulated in these strains?

  • Authors acknowledge microscopy services. There wasn’t any data concerning this service.

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