Uptake and metabolism of antibiotics roseoflavin and 8-demethyl-8-aminoriboflavin in riboflavin-auxotrophic Listeria monocytogenes

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dc.contributor.authorMatern, Andreas
dc.contributor.authorPedrolli, Danielle [UNESP]
dc.contributor.authorGroßhennig, Stephanie
dc.contributor.authorJohansson, Jörgen
dc.contributor.authorMack, Matthias
dc.contributor.institutionMannheim University of Applied Sciences
dc.contributor.institutionUniversidade Estadual Paulista (Unesp)
dc.contributor.institutionUmeå University
dc.date.accessioned2018-12-11T16:44:46Z
dc.date.available2018-12-11T16:44:46Z
dc.date.issued2016-01-01
dc.description.abstractThe riboflavin analogs roseoflavin (RoF) and 8-demethyl-8-aminoriboflavin (AF) are produced by the bacteria Streptomyces davawensis and Streptomyces cinnabarinus. Riboflavin analogs have the potential to be used as broad-spectrum antibiotics, and we therefore studied the metabolism of riboflavin (vitamin B2), RoF, and AF in the human pathogen Listeria monocytogenes, a bacterium which is a riboflavin auxotroph. We show that the L. monocytogenes protein Lmo1945 is responsible for the uptake of riboflavin, RoF, and AF. Following import, these flavins are phosphorylated/adenylylated by the bifunctional flavokinase/flavin adenine dinucleotide (FAD) synthetase Lmo1329 and adenylylated by the unique FAD synthetase Lmo0728, the first monofunctional FAD synthetase to be described in bacteria. Lmo1329 generates the cofactors flavin mononucleotide (FMN) and FAD, whereas Lmo0728 produces FAD only. The combined activities of Lmo1329 and Lmo0728 are responsible for the intracellular formation of the toxic cofactor analogs roseoflavin mononucleotide (RoFMN), roseoflavin adenine dinucleotide (RoFAD), 8-demethyl-8-aminoriboflavin mononucleotide (AFMN), and 8-demethyl-8-aminoriboflavin adenine dinucleotide (AFAD). In vivo reporter gene assays and in vitro transcription/translation experiments show that the L. monocytogenes FMN riboswitch Rli96, which controls expression of the riboflavin transport gene lmo1945, is negatively affected by riboflavin/FMN and RoF/ RoFMN but not by AF/AFMN. Treatment of L. monocytogenes with RoF or AF leads to drastically reduced FMN/FAD levels. We suggest that the reduced flavin cofactor levels in combination with concomitant synthesis of inactive cofactor analogs (RoFMN, RoFAD, AFMN, and AFAD) explain why RoF and AF contribute to antibiotic activity in L. monocytogenes.en
dc.description.affiliationDepartment of Biotechnology Institute for Technical Microbiology Mannheim University of Applied Sciences
dc.description.affiliationDepartment of Bioprocess and Biotechnology School of Pharmaceutical Sciences Universidade Estadual Paulista (UNESP)
dc.description.affiliationLaboratory for Molecular Infection Medicine Sweden (MIMS) Department of Molecular Biology Umeå University
dc.description.affiliationUnespDepartment of Bioprocess and Biotechnology School of Pharmaceutical Sciences Universidade Estadual Paulista (UNESP)
dc.description.sponsorshipBundesministerium für Bildung und Frauen
dc.description.sponsorshipIdBundesministerium für Bildung und Frauen: FKZ0316052A
dc.format.extent3233-3243
dc.identifierhttp://dx.doi.org/10.1128/JB.00388-16
dc.identifier.citationJournal of Bacteriology, v. 198, n. 23, p. 3233-3243, 2016.
dc.identifier.doi10.1128/JB.00388-16
dc.identifier.file2-s2.0-84997207407.pdf
dc.identifier.issn1098-5530
dc.identifier.issn0021-9193
dc.identifier.scopus2-s2.0-84997207407
dc.identifier.urihttp://hdl.handle.net/11449/169171
dc.language.isoeng
dc.relation.ispartofJournal of Bacteriology
dc.relation.ispartofsjr1,885
dc.relation.ispartofsjr1,885
dc.rights.accessRightsAcesso aberto
dc.sourceScopus
dc.titleUptake and metabolism of antibiotics roseoflavin and 8-demethyl-8-aminoriboflavin in riboflavin-auxotrophic Listeria monocytogenesen
dc.typeArtigo

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