Transcription tuned by S-nitrosylation underlies a mechanism for Staphylococcus aureus to circumvent vancomycin killing

Xueqin Shu, Yingying Shi, Yi Huang, Dan Yu () and Baolin Sun ()
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Xueqin Shu: Division of Life Sciences and Medicine, University of Science and Technology of China
Yingying Shi: Division of Life Sciences and Medicine, University of Science and Technology of China
Yi Huang: Division of Life Sciences and Medicine, University of Science and Technology of China
Dan Yu: Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, Key Laboratory of Major Diseases in Children, Ministry of Education, National Center for Children’s Health
Baolin Sun: Division of Life Sciences and Medicine, University of Science and Technology of China

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Treatment of Staphylococcus aureus infections is a constant challenge due to emerging resistance to vancomycin, a last-resort drug. S-nitrosylation, the covalent attachment of a nitric oxide (NO) group to a cysteine thiol, mediates redox-based signaling for eukaryotic cellular functions. However, its role in bacteria is largely unknown. Here, proteomic analysis revealed that S-nitrosylation is a prominent growth feature of vancomycin-intermediate S. aureus. Deletion of NO synthase (NOS) or removal of S-nitrosylation from the redox-sensitive regulator MgrA or WalR resulted in thinner cell walls and increased vancomycin susceptibility, which was due to attenuated promoter binding and released repression of genes involved in cell wall metabolism. These genes failed to respond to H2O2-induced oxidation, suggesting distinct transcriptional responses to alternative modifications of the cysteine residue. Furthermore, treatment with a NOS inhibitor significantly decreased vancomycin resistance in S. aureus. This study reveals that transcriptional regulation via S-nitrosylation underlies a mechanism for NO-mediated bacterial antibiotic resistance.

Date: 2023
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DOI: 10.1038/s41467-023-37949-0

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