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MsrR is a thiol-based oxidation-sensing regulator of the XRE family that modulates C. glutamicum oxidative stress resistance

ABSTRACT: Background Corynebacterium glutamicum thrives under oxidative stress caused by the inevitably extreme environment during fermentation as it harbors antioxidative stress genes. Antioxidant genes are controlled by pathway-specific sensors that act in response to growth conditions. Although many families of oxidation-sensing regulators in C. glutamicum have been well described, members of the xenobiotic-response element (XRE) family, involved in oxidative stress, remain elusive. Results In this study, we report a novel redox-sensitive member of the XER family, MsrR (multiple stress resistance regulator). MsrR is encoded as part of the msrR-3-mst (3-mercaptopyruvate sulfurtransferase) operon; msrR-3-mst is divergent from multidrug efflux protein MFS. MsrR was demonstrated to bind to the intergenic region between msrR-3-mst and mfs. This binding was prevented by an MsrR oxidation-mediated increase in MsrR dimerization. MsrR was shown to use Cys62 oxidation to sense oxidative stress, resulting in its dissociation from the promoter. Elevated expression of msrR-3-mst and mfs was observed under stress. Furthermore, a ?msrR mutant strain displayed significantly enhanced growth, while the growth of strains lacking either 3-mst or mfs was significantly inhibited under stress. Conclusion This report is the first to demonstrate the critical role of MsrR-3-MST-MFS in bacterial stress resistance.

SUBMITTER: Si M

PROVIDER: S-EPMC7532634 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Project description:Streptococcus suis is a zoonotic pathogen that harbors anti-oxidative stress genes, which have been reported to be associated with virulence. Serial passage has been widely used to obtain phenotypic variant strains to investigate the functions of important genes. In the present study, S. suis serotype 9 strain DN13 was serially passaged in mice 30 times. The virulence of a single colony from passage 10 (SS9-P10) was found to increase by at least 140-fold as indicated by LD50 values, and the increased virulence was stable for single colonies from passage 20 (SS0-P20) and 30 (SS0-P30). Compared to the parental strain, the mouse-adapted strains were more tolerant to oxidative and high temperature stress. Genome-wide analysis of nucleotide variations found that reverse mutations occurred in seven genes, as indicated by BLAST analysis. Three of the reverse mutation genes or their homologs in other bacteria were reported to be virulence-associated, including ide Ssuis in S. suis, a homolog of malR of Streptococcus pneumoniae, and a homolog of the prepilin peptidase-encoding gene in Legionella pneumophila. However, these genes were not involved in the stress response. Another gene, srtR (stress response transcriptional regulator), encoding an XRE family transcriptional regulator, which had an internal stop in the parental strain, was functionally restored in the adapted strains. Further analysis of DN13 and SS9-P10-background srtR-knock-out and complementing strains supported the contribution of this gene to stress tolerance in vitro and virulence in mice. srtR and its homologs are widely distributed in Gram-positive bacteria including several important human pathogens such as Enterococcus faecium and Clostridioides difficile, indicating similar functions in these bacteria. Taken together, our study identified the first member of the XRE family of transcriptional regulators that is involved in stress tolerance and virulence. It also provides insight into the mechanism of enhanced virulence after serial passage in experimental animals.

Project description:Oxidative stress serves as an important host/environmental signal that triggers a wide range of responses in microorganisms. Here, we identified an oxidative stress sensor and response regulator in the important multidrug-resistant nosocomial pathogen Enterococcus faecium belonging to the MarR family and called AsrR (antibiotic and stress response regulator). The AsrR regulator used cysteine oxidation to sense the hydrogen peroxide which results in its dissociation to promoter DNA. Transcriptome analysis showed that the AsrR regulon was composed of 181 genes, including representing functionally diverse groups involved in pathogenesis, antibiotic and antimicrobial peptide resistance, oxidative stress, and adaptive responses. Consistent with the upregulated expression of the pbp5 gene, encoding a low-affinity penicillin-binding protein, the asrR null mutant was found to be more resistant to β-lactam antibiotics. Deletion of asrR markedly decreased the bactericidal activity of ampicillin and vancomycin, which are both commonly used to treat infections due to enterococci, and also led to over-expression of two major adhesins, acm and ecbA, which resulted in enhanced in vitro adhesion to human intestinal cells. Additional pathogenic traits were also reinforced in the asrR null mutant including greater capacity than the parental strain to form biofilm in vitro and greater persistance in Galleria mellonella colonization and mouse systemic infection models. Despite overexpression of oxidative stress-response genes, deletion of asrR was associated with a decreased oxidative stress resistance in vitro, which correlated with a reduced resistance to phagocytic killing by murine macrophages. Interestingly, both strains showed similar amounts of intracellular reactive oxygen species. Finally, we observed a mutator phenotype and enhanced DNA transfer frequencies in the asrR deleted strain. These data indicate that AsrR plays a major role in antimicrobial resistance and adaptation for survival within the host, thereby contributes importantly to the opportunistic traits of E. faecium.

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MsrR is a thiol-based oxidation-sensing regulator of the XRE family that modulates C. glutamicum oxidative stress resistance

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