A Natural Compound Containing a Disaccharide Structure of Glucose and Rhamnose Identified as Potential N-Glycanase 1 (NGLY1) Inhibitors.

N-glycanase 1 (NGLY1) is an essential enzyme involved in the deglycosylation of misfolded glycoproteins through the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway, which could hydrolyze N-glycan from N-glycoprotein or N-glycopeptide in the cytosol. Recent studies indicated that NGLY1 inhibition is a potential novel drug target for antiviral therapy. In this study, structure-based virtual analysis was applied to screen candidate NGLY1 inhibitors from 2960 natural compounds. Three natural compounds, Poliumoside, Soyasaponin Bb, and Saikosaponin B2 showed significantly inhibitory activity of NGLY1, isolated from traditional heat-clearing and detoxifying Chinese herbs. Furthermore, the core structural motif of the three NGLY1 inhibitors was a disaccharide structure with glucose and rhamnose, which might exert its action by binding to important active sites of NGLY1, such as Lys238 and Trp244. In traditional Chinese medicine, many compounds containing this disaccharide structure probably targeted NGLY1. This study unveiled the leading compound of NGLY1 inhibitors with its core structure, which could guide future drug development.

Genomic characterization of Salmonella enterica serovar Kentucky and London recovered from food and human salmonellosis in Zhejiang Province, China (2016-2021).

Increasing human salmonellosis caused by Salmonella enterica serovar Kentucky and London has raised serious concerns. To better understand possible health risks, insights were provided into specific genetic traits and antimicrobial resistance of 88 representative isolates from human and food sources in Zhejiang Province, China, during 2016-2021. Phylogenomic analysis revealed consistent clustering of isolates into the respective serovar or sequence types, and identified plausible interhost transmission via distinct routes. Each serovar exhibited remarkable diversity in host range and disease-causing potential by cgMLST analyses, and approximately half (48.6%, 17/35) of the food isolates were phylogenetically indistinguishable to those of clinical isolates in the same region. S. London and S. Kentucky harbored serovar-specific virulence genes contributing to their functions in pathogenesis. The overall resistance genotypes correlated with 97.7% sensitivity and 60.2% specificity to the identified phenotypes. Resistance to ciprofloxacin, cefazolin, tetracycline, ampicillin, azithromycin, chloramphenicol, as well as multidrug resistance, was common. High-level dual resistance to ciprofloxacin and cephalosporins in S. Kentucky ST198 isolates highlights evolving threats of antibiotic resistance. These findings underscored the necessity for the development of effective strategies to mitigate the risk of food contamination by Salmonella host-restricted serovars.