Modulation of antibiotic sensitivity and biofilm formation in Pseudomonas aeruginosa by interspecies signal analogues

dc.contributor.authorAn, Shi-qi
dc.contributor.authorMurtagh, Julie
dc.contributor.authorTwomey, Kate B.
dc.contributor.authorGupta, Manoj K.
dc.contributor.authorO'Sullivan, Timothy P.
dc.contributor.authorIngram, Rebecca
dc.contributor.authorValvano, Miguel A.
dc.contributor.authorTang, Ji-liang
dc.contributor.funderWellcome Trusten
dc.contributor.funderEducation Department of Guangxi Zhuang Autonomous Regionen
dc.contributor.funderBiotechnology and Biological Sciences Research Councilen
dc.date.accessioned2019-09-25T08:42:44Z
dc.date.available2019-09-25T08:42:44Z
dc.date.issued2019-05-27
dc.date.updated2019-09-19T16:59:48Z
dc.description.abstractPseudomonas aeruginosa, a significant opportunistic pathogen, can participate in inter-species communication through signaling by cis-2-unsaturated fatty acids of the diffusible signal factor (DSF) family. Sensing these signals leads to altered biofilm formation and increased tolerance to various antibiotics, and requires the histidine kinase PA1396. Here, we show that the membrane-associated sensory input domain of PA1396 has five transmembrane helices, two of which are required for DSF sensing. DSF binding is associated with enhanced auto-phosphorylation of PA1396 incorporated into liposomes. Further, we examined the ability of synthetic DSF analogues to modulate or inhibit PA1396 activity. Several of these analogues block the ability of DSF to trigger auto-phosphorylation and gene expression, whereas others act as inverse agonists reducing biofilm formation and antibiotic tolerance, both in vitro and in murine infection models. These analogues may thus represent lead compounds to develop novel adjuvants improving the efficacy of existing antibiotics.en
dc.description.sponsorshipWellcome Trust (Grant 100204/A/12/Z); Education Department of Guangxi Zhuang Autonomous Region (Ba Gui Scholar Program 2014A002); Biotechnology and Biological Sciences Research Council (Grant BB/R012415/1)en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.articleid2334en
dc.identifier.citationAn, S.-q., Murtagh, J., Twomey, K. B., Gupta, M. K., O'Sullivan, T. P., Ingram, R., Valvano, M. A. and Tang, J. L. (2019) 'Modulation of antibiotic sensitivity and biofilm formation in Pseudomonas aeruginosa by interspecies signal analogues', Nature Communications, 10, 2334 (11pp). doi: 10.1038/s41467-019-10271-4en
dc.identifier.doi10.1038/s41467-019-10271-4en
dc.identifier.endpage11en
dc.identifier.issn2041-1723
dc.identifier.journaltitleNature Communicationsen
dc.identifier.startpage1en
dc.identifier.urihttps://hdl.handle.net/10468/8613
dc.identifier.volume10en
dc.language.isoenen
dc.publisherSpringer Nature Limiteden
dc.rights© 2019, the Authors. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third-party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en
dc.subjectStructure predictionen
dc.subjectMembrane-proteinsen
dc.subjectSensor kinaseen
dc.subjectBacterialen
dc.subjectVirulenceen
dc.subjectGenesen
dc.subjectReconstitutionen
dc.subjectTobramycinen
dc.subjectTopologyen
dc.subjectMoleculeen
dc.titleModulation of antibiotic sensitivity and biofilm formation in Pseudomonas aeruginosa by interspecies signal analoguesen
dc.typeArticle (peer-reviewed)en
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