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Nitrate Reductase NarGHJI Modulates Vancomycin Susceptibility by Coordinating Cell Wall Remodeling and Agmatine Metabolism in Staphylococcus aureus

ABSTRACT: Staphylococcus aureus is a ubiquitous pathogen responsible for a wide range of severe infections. Our previous work established that the nitrate reductase NarGHJI modulates bacterial pathogenicity through regulation of the agr system, yet its role in antibiotic resistance remains poorly understood. In this study, we investigated whether NarGHJI influences susceptibility to vancomycin of S. aureus. Disruption of narG significantly reduced vancomycin susceptibility, prompting us to explore the underlying mechanisms. Phenotypic analyses revealed that the ΔnarG mutant possessed a markedly thickened cell wall and exhibited a decreased autolysis rate compared to the wild-type strain. Consistently, RT-qPCR showed a distinct transcriptional reprogramming: autolysis-related genes (lytN and ssaA) were significantly downregulated, while the cell wall synthesis gene dltA was upregulated. Furthermore, we uncovered that NarGHJI regulates vancomycin susceptibility through agmatine metabolism, which in turn reduces the net negative surface charge of S. aureus cells, ultimately impairing vancomycin binding to the cell wall. Notably, this NarGHJI-mediated resistance mechanism appeared to be strain-dependent to some extent. Collectively, our findings reveal a novel regulatory axis linking NarGHJI to vancomycin resistance, suggesting this enzyme complex as a potential therapeutic target for combating S. aureus infections.

INSTRUMENT(S): Liquid Chromatography MS - positive - hilic, Liquid Chromatography MS - negative - hilic

PROVIDER: MTBLS14968 | MetaboLights | 2026-07-07

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS14968_LC-MS_negative_hilic.txt	Txt
	a_MTBLS14968_LC-MS_positive_hilic.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS14968_LC-MS_negative_hilic_v2_maf.tsv	Tabular
	m_MTBLS14968_LC-MS_positive_hilic_v2_maf.tsv	Tabular

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Project description:The phenotype “intermediate vancomycin resistance” in Staphylococcus aureus (CLSI: MIC = 4-8 mg/L) has been assigned to changes that lead to alterations in cell wall synthesis and morphology. Most vancomycin intermediately resistant S. aureus (VISA) strains are characterised by an increased cell wall thickness as a consequence of an activated cell wall biosynthesis and decreased autolysis. The purpose of this study was to analyse the genetic basis of the vancomycin resistance mechanism of the clinical VISA isolate SA137/93A and its spontaneous mutant strain SA137/93G. The methicillin-resistant S. aureus (MRSA) SA137/93A was isolated from a tracheal secretion and displays heterogeneous intermediate vancomycin resistance (hVISA strain, MIC: 8 mg/L in BHI). Subculturing in presence of 6 mg/L vancomycin generated a mutant with homogeneous intermediate vancomycin resistance, that showed an MIC value of 16 mg/L in BHI and was designated SA137/93G. PFGE profiles and phage typing of the strains showed that they were members of the Iberian clone (ST247), which was prevalent in Germany in the early nineties under the designation “Northern German epidemic strain”. Both strains possess a thickened cell wall. However, the vancomycin resistance of strain SA137/93A is most probably enhanced by an increased amount of free D-Ala-D-Ala termini in the cell wall, which is due to decreased crosslinking, whereas the mutant strain SA137/93G shows normal crosslinking. Moreover, strain SA137/93A displays an increased expression of the essential two-component system yycFGHI as a consequence of an IS256 insertion in the promoter region, while strain SA137/93G is characterised by an insertion of IS256 into the gene tcaA. Although both insertions were shown to correlate with a decrease in susceptibility to vancomycin, the difference in the vancomycin resistance level of the strain pair could be mainly attributed to the disruption of tcaA in the mutant.This study was conducted to identify resistance mechanisms that both strains might have in common. To this end we compared the transcriptomes of both strains with that of the closely related vancomycin susceptible MRSA/VSSA strain SA1450/94 (MIC: 2 mg/L). We found that the genes of the capsule biosynthesis were the only genes with higher expression in both VISA strains. Keywords: strain comparison

Dataset Information

Nitrate Reductase NarGHJI Modulates Vancomycin Susceptibility by Coordinating Cell Wall Remodeling and Agmatine Metabolism in Staphylococcus aureus

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