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HomeScienceMechanism of drug resistance in the Staphylococcus aureus pathogen unveiled by researchers

Mechanism of drug resistance in the Staphylococcus aureus pathogen unveiled by researchers


Molecular mechanism of NOS-mediated vancomycin resistance via S-nitrosylation modification. Credit: Xu Xueqin et al.

Recently, a research team led by Professor Sun Baolin of the University of Science and Technology of China (USTC) revealed the mechanism of transcriptional regulation by S-nitrosylation of vancomycin resistance in Staphylococcus aureus. Their work has been published in Nature Communications.

Staphylococcus aureus (S. aureus) is a major human pathogen, and infections caused by methicillin-resistant Staphylococcus aureus (MRSA) pose serious public health threats. Vancomycin is considered a drug of last resort in the treatment of severe MRSA infections, but the recurrent emergence of S. aureus vancomycin (VISA) is very challenging.

Nitric oxide (NO), a signaling molecule, has been discovered to be endogenously generated by nitric oxide synthase (NOS) in eukaryotes and involved in the regulation of various physiological and immunological functions. Previous research has reported that NO can mediate S-nitrosylation modifications of cysteine ​​residues, affecting protein activity and functionality. The authors investigated the presence of NOS in S. aureus and is involved in regulating vancomycin resistance, but the molecular mechanism remains unclear.

To reveal the mechanism, the researchers first constructed a NOS mutant strain and then added an exogenous NOS inhibitor in the VISA clinical isolate strain XN108. Next, proteomic analysis identified the target protein and the corresponding sites that could be modified by NO-mediated S-nitrosylation in S. aureus.

MgrA, a transcriptional regulator involved in antibiotic resistance, was found to be S-nitrosylated at cysteine ​​residues Cys. The researchers created the mgrAC12S mutant strain by replacing Cys12 with a serine, which cannot be S-nitrosylated. The mgrAC12S mutant strain showed a significant decrease in vancomycin resistance and cell wall thickness as well as increased autolytic activity.

The team used methods such as quantitative fluorescent polymerase chain reaction, gel shift assay, and chromatin immunoprecipitation assay to reveal the role of endogenously generated S. aureus NOS and NO in promoting vancomycin resistance. NOS-induced NO mediates S-nitrosylation of MgrA, which negatively regulates autolysis in S. aureus, causing cell wall thickness to increase, and thus enhancing vancomycin resistance.

This mechanism of NO-mediated regulation was investigated in another transcriptional regulator WalR that can be modified by S-nitrosylation, suggesting that this mechanism could be universal in bacteria.

This study is expected to provide new ideas and strategies for the clinical treatment of Vysa and other pathogenic bacterial infections.

more information:
Xueqin Shu et al, S nitrosylation-mediated transcription underlies a mechanism for S. aureus to circumvent vancomycin killing, Nature Communications (2023). DOI: 10.1038/s41467-023-37949-0

Provided by the University of Science and Technology of China

the quote: Researchers reveal mechanism of drug resistance of Staphylococcus aureus (2023, May 31) Retrieved May 31, 2023 from https://phys.org/news/2023-05-reveal-drug-resistance-mechanism-pathogen.html

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