AbstractBronchopneumonia is the most common pneumonia in childhood. Therefore, we tested the effects of Remimazolam presented Bronchopneumonia and its possible mechanisms. Phillygenin increased survival rate, reduced W/D ratio, and lung injury score, and inhibited IL‐1β, IL‐6, TNF‐α, and INF‐γ levels in mice model of bronchopneumonia. Remimazolam induced PDPK1 and p‐AKT protein expressions, and suppressed NLRP3 protein expression in lung tissue of mice model. In vitro model, Remimazolam also induced PDPK1 and p‐AKT protein expressions, and suppressed NLRP3 protein expression. Remimazolam also inhibited inflammation levels in vitro model. PDPK1 inhibitor, PHT‐427 (100 mg/kg) reduced survival rate, increased W/D ratio and lung injury score, and promoted inflammation levels in mice model of bronchopneumonia by treated with Remimazolam. PHT‐427 suppressed PDPK1 and p‐AKT protein expressions and induced NLRP3 protein expression in mice model of bronchopneumonia by treated with Remimazolam. Remimazolam interlinked PDPK1 protein. Remimazolam increased the expressions of PDPK1 and p‐AKT in vitro model. Remimazolam reduced PDPK1 ubiquitination in vitro model.

2023-01-01·Frontiers in microbiology

PHT427 as an effective New Delhi metallo-β-lactamase-1 (NDM-1) inhibitor restored the susceptibility of meropenem against Enterobacteriaceae producing NDM-1.

Article

作者: Guan, Yan ; Han, Jiangxue ; Wang, Xiao ; Liu, Sihan ; Liu, Tianjun ; Liu, Yishuang ; Li, Xiaohui ; Zheng, Ji ; Liu, Chennan ; Wang, Qian ; Xiao, Chunling

IntroductionWith the increasingly serious problem of bacterial drug resistance caused by NDM-1, it is an important strategy to find effective inhibitors to assist β-lactam antibiotic treatment against NDM-1 resistant bacteria. In this study, PHT427 (4-dodecyl-N-1,3,4-thiadiazol-2-yl-benzenesulfonamide) was identified as a novel NDM-1 inhibitor and restored the susceptibility of meropenem against Enterobacteriaceae producing NDM-1.MethodsWe used a high throughput screening model to find NDM-1 inhibitor in the library of small molecular compounds. The interaction between the hit compound PHT427 and NDM-1 was analyzed by fluorescence quenching, surface plasmon resonance (SPR) assay, and molecular docking analysis. The efficacy of the compound in combination with meropenem was evaluated by determining the FICIs of Escherichia coli BL21(DE3)/pET30a(+)-bla _NDM-1 and Klebsiella pneumoniae clinical strain C1928 (producing NDM-1). In addition, the mechanism of the inhibitory effect of PHT427 on NDM-1 was studied by site mutation, SPR, and zinc supplementation assays.ResultsPHT427 was identified as an inhibitor of NDM-1. It could significantly inhibit the activity of NDM-1 with an IC₅₀ of 1.42 μmol/L, and restored the susceptibility of meropenem against E. coli BL21(DE3)/pET30a(+)-bla _NDM-1 and K. pneumoniae clinical strain C1928 (producing NDM-1) in vitro. The mechanism study indicated that PHT427 could act on the zinc ions at the active site of NDM-1 and the catalytic key amino acid residues simultaneously. The mutation of Asn220 and Gln123 abolished the affinity of NDM-1 by PHT427 via SPR assay.DiscussionThis is the first report that PHT427 is a promising lead compound against carbapenem-resistant bacteria and it merits chemical optimization for drug development.

2021-09-01·Journal of Agricultural and Food Chemistry1区 · 农林科学

Identification of a New Antimicrobial Agent against Bovine Mastitis-Causing Staphylococcus aureus

1区 · 农林科学

Article

作者: Kim, Younghoon ; Payne, Shelley M. ; Mun, Daye ; Kim, Sooah ; Choi, Hye Jin ; Shin, Minhye

Staphylococcus aureus RF122 is a major pathogen that causes bovine mastitis, which is the most prevalent and costly disease in the milk and dairy industry. S. aureus expresses various virulence factors that are especially highly associated with iron metabolism, and the bacterial ferrous iron transport system Feo is important for bacterial growth or virulence in mammalian hosts. In this study, we evaluated a new antimicrobial agent, PHT-427, targeting the S. aureus RF122 Feo system for the prevention of bovine mastitis. Various analyses on in vitro enzymatic assays, growth inhibition, virulence expressions, and toxicity of animal model systems were conducted to characterize the inhibition properties of PHT-427. This small molecule efficiently inhibited enzyme activity of FeoB and bacterial growth. PHT-427 attenuated various virulence factors related to milk quality, including staphyloxanthin production, biofilm formation, and coagulation. Considering the high frequency of antibiotic-resistant S. aureus in bovine mastitis isolates, PHT-427 synergistically enhanced bacterial antibiotic susceptibility and further inhibited global Gram-positive bacterial growth. Unlike its effects on bacteria, the inhibitor did not show any toxicity on animal model systems. These results indicate that the S. aureus Feo system represents a good target for antimicrobial strategies, and this new antimicrobial agent may represent a promising biotechnological application for preventing S. aureus-induced bovine mastitis in the milk and dairy industry.

100 项与 PH-427 相关的药物交易

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