{"title":"在硅预测的铜绿假单胞菌LasR或一氧化氮还原酶(NOR)小分子抑制剂中鉴定抗致病活性。","authors":"Gemini Gajera, Niel Henriksen, Bryan Cox, Vijay Kothari","doi":"10.33393/dti.2023.2638","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>Antibiotic-resistant <i>Pseudomonas aeruginosa</i> strains cause considerable morbidity and mortality globally. Identification of novel targets in this notorious pathogen is urgently warranted to facilitate discovery of new anti-pathogenic agents against it. This study attempted to identify small-molecule inhibitors of two important proteins LasR and nitric oxide reductase (NOR) in <i>P. aeruginosa</i>. 'Las' system can be said to be the 'master' regulator of quorum sensing in <i>P. aeruginosa</i>, whose receptor protein is LasR. Similarly, NOR is crucial to detoxification of reactive nitrogen species.</p><p><strong>Methods: </strong><i>In silico</i> identification of potential LasR or NOR inhibitors was attempted through a virtual screening platform AtomNet® to obtain a final subset of <100 top scoring compounds. These compounds were evaluated for their <i>in vivo</i> anti-pathogenic activity by challenging the model host <i>Caenorhabditis elegans</i> with <i>P. aeruginosa</i> in the presence or absence of test compounds. Survival of the worm population in 24-well assay plates was monitored over a period of 5 days microscopically.</p><p><strong>Results: </strong>Of the 96 predicted LasR inhibitors, 11 exhibited anti-<i>Pseudomonas</i> activity (23%-96% inhibition of bacterial virulence as per third-day end-point) at 25-50 µg/mL. Of the 85 predicted NOR inhibitors, 8 exhibited anti-<i>Pseudomonas</i> activity (40%-85% inhibition of bacterial virulence as per second-day end-point) at 25-50 µg/mL.</p><p><strong>Conclusion: </strong>Further investigation on molecular mode of action of compounds found active in this study is warranted. Virtual screening can be said to be a useful tool in narrowing down the list of compounds requiring actual wet-lab screening, saving considerable time and efforts for drug discovery.</p>","PeriodicalId":11326,"journal":{"name":"Drug Target Insights","volume":null,"pages":null},"PeriodicalIF":2.0000,"publicationDate":"2023-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/bf/04/dti-17-101.PMC10551673.pdf","citationCount":"0","resultStr":"{\"title\":\"Identification of anti-pathogenic activity among <i>in silico</i> predicted small-molecule inhibitors of <i>Pseudomonas aeruginosa</i> LasR or nitric oxide reductase (NOR).\",\"authors\":\"Gemini Gajera, Niel Henriksen, Bryan Cox, Vijay Kothari\",\"doi\":\"10.33393/dti.2023.2638\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>Antibiotic-resistant <i>Pseudomonas aeruginosa</i> strains cause considerable morbidity and mortality globally. Identification of novel targets in this notorious pathogen is urgently warranted to facilitate discovery of new anti-pathogenic agents against it. This study attempted to identify small-molecule inhibitors of two important proteins LasR and nitric oxide reductase (NOR) in <i>P. aeruginosa</i>. 'Las' system can be said to be the 'master' regulator of quorum sensing in <i>P. aeruginosa</i>, whose receptor protein is LasR. Similarly, NOR is crucial to detoxification of reactive nitrogen species.</p><p><strong>Methods: </strong><i>In silico</i> identification of potential LasR or NOR inhibitors was attempted through a virtual screening platform AtomNet® to obtain a final subset of <100 top scoring compounds. These compounds were evaluated for their <i>in vivo</i> anti-pathogenic activity by challenging the model host <i>Caenorhabditis elegans</i> with <i>P. aeruginosa</i> in the presence or absence of test compounds. Survival of the worm population in 24-well assay plates was monitored over a period of 5 days microscopically.</p><p><strong>Results: </strong>Of the 96 predicted LasR inhibitors, 11 exhibited anti-<i>Pseudomonas</i> activity (23%-96% inhibition of bacterial virulence as per third-day end-point) at 25-50 µg/mL. Of the 85 predicted NOR inhibitors, 8 exhibited anti-<i>Pseudomonas</i> activity (40%-85% inhibition of bacterial virulence as per second-day end-point) at 25-50 µg/mL.</p><p><strong>Conclusion: </strong>Further investigation on molecular mode of action of compounds found active in this study is warranted. Virtual screening can be said to be a useful tool in narrowing down the list of compounds requiring actual wet-lab screening, saving considerable time and efforts for drug discovery.</p>\",\"PeriodicalId\":11326,\"journal\":{\"name\":\"Drug Target Insights\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.0000,\"publicationDate\":\"2023-09-28\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/bf/04/dti-17-101.PMC10551673.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Drug Target Insights\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.33393/dti.2023.2638\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2023/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q3\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Drug Target Insights","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.33393/dti.2023.2638","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/1/1 0:00:00","PubModel":"eCollection","JCR":"Q3","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Identification of anti-pathogenic activity among in silico predicted small-molecule inhibitors of Pseudomonas aeruginosa LasR or nitric oxide reductase (NOR).
Introduction: Antibiotic-resistant Pseudomonas aeruginosa strains cause considerable morbidity and mortality globally. Identification of novel targets in this notorious pathogen is urgently warranted to facilitate discovery of new anti-pathogenic agents against it. This study attempted to identify small-molecule inhibitors of two important proteins LasR and nitric oxide reductase (NOR) in P. aeruginosa. 'Las' system can be said to be the 'master' regulator of quorum sensing in P. aeruginosa, whose receptor protein is LasR. Similarly, NOR is crucial to detoxification of reactive nitrogen species.
Methods: In silico identification of potential LasR or NOR inhibitors was attempted through a virtual screening platform AtomNet® to obtain a final subset of <100 top scoring compounds. These compounds were evaluated for their in vivo anti-pathogenic activity by challenging the model host Caenorhabditis elegans with P. aeruginosa in the presence or absence of test compounds. Survival of the worm population in 24-well assay plates was monitored over a period of 5 days microscopically.
Results: Of the 96 predicted LasR inhibitors, 11 exhibited anti-Pseudomonas activity (23%-96% inhibition of bacterial virulence as per third-day end-point) at 25-50 µg/mL. Of the 85 predicted NOR inhibitors, 8 exhibited anti-Pseudomonas activity (40%-85% inhibition of bacterial virulence as per second-day end-point) at 25-50 µg/mL.
Conclusion: Further investigation on molecular mode of action of compounds found active in this study is warranted. Virtual screening can be said to be a useful tool in narrowing down the list of compounds requiring actual wet-lab screening, saving considerable time and efforts for drug discovery.