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Chemical inhibitors of the conserved bacterial transcriptional regulator DksA1 suppressed quorum sensing-mediated virulence of Pseudomonas aeruginosa

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dc.contributor.author윤상선-
dc.contributor.author이강무-
dc.contributor.author이강무-
dc.contributor.author황원태-
dc.date.accessioned2021-09-29T01:05:23Z-
dc.date.available2021-09-29T01:05:23Z-
dc.date.issued2021-03-
dc.identifier.issn0021-9258-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/184188-
dc.description.abstractPseudomonas aeruginosa is a Gram-negative opportunistic pathogen whose virulence is dependent on quorum sensing (QS). DksA1, an RNA polymerase-binding transcriptional regulator, plays a role in determining a number of phenotypes, including QS-mediated virulence. We therefore envisioned that DksA1 inhibitors may help to control P. aeruginosa infection. Here, we screened a library of 6970 chemical compounds and identified two compounds (henceforth termed Dkstatins) that specifically suppressed DksA1 activity. Treatment with these two compounds also substantially decreased the production of elastase and pyocyanin, dominant virulence determinants of P. aeruginosa, and protected murine hosts from lethal infection from a prototype strain of P. aeruginosa, PAO1. The Dkstatins also suppressed production of homoserine lactone (HSL)-based autoinducers that activate P. aeruginosa QS. The level of 3-oxo-C12-HSL produced by Dkstatin-treated wildtype PAO1 closely resembled that of the ΔdksA1 mutant. RNA-Seq analysis showed that transcription levels of QS- and virulence-associated genes were markedly reduced in Dkstatin-treated PAO1 cells, indicating that Dkstatin-mediated suppression occurs at the transcriptional level. Importantly, Dkstatins increased the antibiotic susceptibilities of PAO1, particularly to protein synthesis inhibitors, such as tobramycin and tetracycline. Co-immunoprecipitation assays demonstrated that these Dkstatins interfered with DksA1 binding to the β subunit of RNA polymerase, pointing to a potential mechanism of action. Collectively, our results illustrate that inhibition of P. aeruginosa QS may be achieved via DksA1 inhibitors and that Dkstatins may serve as potential lead compounds to control infection.-
dc.description.statementOfResponsibilityopen-
dc.formatapplication/pdf-
dc.languageEnglish-
dc.publisherAmerican Society for Biochemistry and Molecular Biology-
dc.relation.isPartOfJOURNAL OF BIOLOGICAL CHEMISTRY-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.titleChemical inhibitors of the conserved bacterial transcriptional regulator DksA1 suppressed quorum sensing-mediated virulence of Pseudomonas aeruginosa-
dc.typeArticle-
dc.contributor.collegeCollege of Medicine (의과대학)-
dc.contributor.departmentDept. of Microbiology (미생물학교실)-
dc.contributor.googleauthorKyung Bae Min-
dc.contributor.googleauthorWontae Hwang-
dc.contributor.googleauthorKang-Mu Lee-
dc.contributor.googleauthorJune Beom Kim-
dc.contributor.googleauthorSang Sun Yoon-
dc.identifier.doi10.1016/j.jbc.2021.100576-
dc.contributor.localIdA02558-
dc.contributor.localIdA02638-
dc.contributor.localIdA02638-
dc.relation.journalcodeJ01258-
dc.identifier.eissn1083-351X-
dc.identifier.pmid33757766-
dc.subject.keywordDksA1-
dc.subject.keywordPseudomonas aeruginosa-
dc.subject.keywordquorums sensing-
dc.subject.keywordstringent response-
dc.subject.keywordtranscriptional factor-
dc.subject.keywordvirulence factor-
dc.contributor.alternativeNameYoon, Sang Sun-
dc.contributor.affiliatedAuthor윤상선-
dc.contributor.affiliatedAuthor이강무-
dc.contributor.affiliatedAuthor이강무-
dc.citation.volume296-
dc.citation.number1-
dc.citation.startPage100576-
dc.identifier.bibliographicCitationJOURNAL OF BIOLOGICAL CHEMISTRY, Vol.296(1) : 100576, 2021-03-
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers

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