Search

In this study, umami peptides were screened and characterized from bovine bone soups manufactured via atmospheric and high-pressure boiling. Peptide fractions with molecular weights less than 3 kDa were selected for peptide sequencing using LC-MS/MS, the toxicity prediction of the umami peptides was carried out by using an website, and the peptides were screened according to the binding energy, i.e., three peptides including YDAELS, TDVAHR, and ELELQ were selected. The three umami peptides were further synthesized, and their umami thresholds were determined through sensory evaluation and electronic tongue analysis, ranging from 0.375 to 0.75 mg/mL. All three peptides exhibited a significant synergistic taste enhancement effect when combined with MSG (monosodium glutamate) solution. The molecular docking of the umami peptides with the T1R1/T1R3 receptor revealed the mechanism of umami presentation, and the main interaction forces between the three umami peptides and the receptor were hydrogen bonding, electrostatic interactions, and hydrophobic interactions. [ABSTRACT FROM AUTHOR]

Background and Purpose: At present, the inhibition of staphyloxanthin biosynthesis has emerged as a prominent strategy in combating methicillin‐resistant Staphylococcus aureus (MRSA) infection. Nonetheless, there remains a limited understanding regarding the bio‐structural characteristics of staphyloxanthin biosynthetic enzymes, as well as the molecular mechanisms underlying the interaction between inhibitors and proteins. Furthermore, the functional scope of these inhibitors is relatively narrow. Experimental Approach: In this study, we address these limitations by harnessing the power of deep learning techniques to construct the 3D structure of diapophytoene desaturase (CrtN). We perform efficient virtual screening and unveil alnustone as a potent inhibitor of CrtN. Further investigations employing molecular modelling, site‐directed mutagenesis and biolayer interferometry (BLI) confirmed that alnustone binds to the catalytic active site of CrtN. Transcriptomic analysis reveals that alnustone significantly down‐regulates genes associated with staphyloxanthin, histidine and peptidoglycan biosynthesis. Key Results: Under the effects of alnustone, MRSA strains exhibit enhanced sensitivity to various antibiotics and the host immune system, accompanied by increased cell membrane permeability. In a mouse model of systemic MRSA infection, the combination of alnustone and antibiotics exhibited a significant therapeutic effect, leading to reduced bacterial colony counts and attenuated pathological damage. Conclusion and Implications: Alnustone, as a natural inhibitor targeting CrtN, exhibits outstanding antibacterial properties that are single‐targeted yet multifunctional. This finding provides a novel strategy and theoretical basis for the development of drugs targeting staphyloxanthin producing bacteria. [ABSTRACT FROM AUTHOR]

Background and purpose: The production of metallo‐β‐lactamases is a major mechanisms adopted by bacterial pathogens to resist carbapenems. Repurposing approved drugs to restore the efficacy of carbapenems represents an efficient and cost‐effective approach to fight infections caused by carbapenem resistant pathogens. Experimental approach: The nitrocefin hydrolysis assay was employed to screen potential New Delhi metallo‐lactamase‐1 (NDM‐1) inhibitors from a commercially available U.S. Food and Drug Administration (FDA) approved drug library. The mechanism of inhibition was clarified by metal restoration, inductively coupled plasma mass spectrometry (ICP‐MS) and molecular dynamics simulation. The in vitro synergistic antibacterial effect of the identified inhibitors with meropenem was determined by the checkerboard minimum inhibitory concentration (MIC) assay, time‐dependent killing assay and combined disc test. Three mouse infection models were used to further evaluate the in vivo therapeutic efficacy of combined therapy. Key results: Twelve FDA‐approved compounds were initially screened to inhibit the ability of NDM‐1 to hydrolyse nitrocefin. Among these compounds, dexrazoxane, embelin, candesartan cilexetil and nordihydroguaiaretic acid were demonstrated to inhibit all tested metallo‐β‐lactamases and showed an in vitro synergistic bactericidal effect with meropenem against metallo‐β‐lactamases‐producing bacteria. Dexrazoxane, embelin and candesartan cilexetil are metal ion chelating agents, while the inhibition of NDM‐1 by nordihydroguaiaretic acid involves its direct binding to the active region of NDM‐1. Furthermore, these four drugs dramatically rescued the treatment efficacy of meropenem in three infection models. Conclusions and implications: Our observations indicated that dexrazoxane, embelin, candesartan cilexetil and nordihydroguaiaretic acid are promising carbapenem adjuvants against metallo‐β‐lactamases‐positive carbapenem resistant bacterial pathogens. [ABSTRACT FROM AUTHOR]

Currently, allosteric inhibitors have emerged as an effective strategy in the development of preservatives against the drug-resistant Botrytis cinerea ( B. cinerea ). However, their passively driven development efficiency has proven challenging to meet the practical demands. Here, leveraging the deep learning Neural Relational Inference (NRI) framework, we actively identified an allosteric inhibitor targeting B. cinerea Chitinase, namely, 2-acetonaphthone. 2-Acetonaphthone binds to the crucial domain of Chitinase, forming the strong interaction with the allosteric sites. Throughout the interaction process, 2-acetonaphthone diminished the overall connectivity of the protein, inducing conformational changes. These findings align with the results obtained from Chitinase activity experiments, revealing an IC 50 value of 67.6 μg/mL. Moreover, 2-acetonaphthone exhibited outstanding anti- B. cinerea activity by inhibiting Chitinase. In the gray mold infection model, 2-acetonaphthone significantly extended the preservation time of cherry tomatoes, positioning it as a promising preservative for fruit storage.