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dc.contributor.authorPopella, Linda
dc.contributor.authorJung, Jakob
dc.contributor.authorPopova, Kristina
dc.contributor.authorÐurica-Mitić, Svetlana
dc.contributor.authorBarquist, Lars
dc.contributor.authorVogel, Jörg
dc.date.accessioned2021-06-08T11:39:42Z
dc.date.available2021-06-08T11:39:42Z
dc.identifier.pmid33849070
dc.identifier.doi10.1093/nar/gkab242
dc.identifier.urihttp://hdl.handle.net/10033/622899
dc.description.abstractAntisense peptide nucleic acids (PNAs) inhibiting mRNAs of essential genes provide a straight-forward way to repurpose our knowledge of bacterial regulatory RNAs for development of programmable species-specific antibiotics. While there is ample proof of PNA efficacy, their target selectivity and impact on bacterial physiology are poorly understood. Moreover, while antibacterial PNAs are typically designed to block mRNA translation, effects on target mRNA levels are not well-investigated. Here, we pioneer the use of global RNA-seq analysis to decipher PNA activity in a transcriptome-wide manner. We find that PNA-based antisense oligomer conjugates robustly decrease mRNA levels of the widely-used target gene, acpP, in Salmonella enterica, with limited off-target effects. Systematic analysis of several different PNA-carrier peptides attached not only shows different bactericidal efficiency, but also activation of stress pathways. In particular, KFF-, RXR- and Tat-PNA conjugates especially induce the PhoP/Q response, whereas the latter two additionally trigger several distinct pathways. We show that constitutive activation of the PhoP/Q response can lead to Tat-PNA resistance, illustrating the utility of RNA-seq for understanding PNA antibacterial activity. In sum, our study establishes an experimental framework for the design and assessment of PNA antimicrobials in the long-term quest to use these for precision editing of microbiota.en_US
dc.language.isoenen_US
dc.publisherOxford University Pressen_US
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.titleGlobal RNA profiles show target selectivity and physiological effects of peptide-delivered antisense antibiotics.en_US
dc.typeArticleen_US
dc.identifier.eissn1362-4962
dc.contributor.departmentHIRI, Helmholtz-Institut für RNA-basierte Infektionsforschung, Josef-Shneider Strasse 2, 97080 Würzburg, Germany.en_US
dc.identifier.journalNucleic acids researchen_US
dc.source.volume49
dc.source.issue8
dc.source.beginpage4705
dc.source.endpage4724
refterms.dateFOA2021-06-08T11:39:42Z
dc.source.journaltitleNucleic acids research
dc.source.countryEngland


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Attribution 4.0 International
Except where otherwise noted, this item's license is described as Attribution 4.0 International