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dc.contributor.authorTestolin, Giambattista
dc.contributor.authorCirnski, Katarina
dc.contributor.authorRox, Katharina
dc.contributor.authorProchnow, Hans
dc.contributor.authorFetz, Verena
dc.contributor.authorGrandclaudon, Charlotte
dc.contributor.authorMollner, Tim
dc.contributor.authorBaiyoumy, Alain
dc.contributor.authorRitter, Antje
dc.contributor.authorLeitner, Christian
dc.contributor.authorKrull, Jana
dc.contributor.authorvan den Heuvel, Joop
dc.contributor.authorVassort, Aurelie
dc.contributor.authorSordello, Sylvie
dc.contributor.authorHamed, Mostafa M.
dc.contributor.authorElgaher, Walid A.M.
dc.contributor.authorHerrmann, Jennifer
dc.contributor.authorHartmann, Rolf W.
dc.contributor.authorMüller, Rolf
dc.contributor.authorBrönstrup, Mark
dc.date.accessioned2020-11-06T14:53:02Z
dc.date.available2020-11-06T14:53:02Z
dc.date.issued2020-01-01
dc.identifier.citationChem. Sci (2020);11(5);DOI:10.1039/C9SC04769G.en_US
dc.identifier.issn20416520
dc.identifier.doi10.1039/c9sc04769g
dc.identifier.urihttp://hdl.handle.net/10033/622562
dc.description.abstractThere is an alarming scarcity of novel chemical matter with bioactivity against multidrug-resistant Gram-negative bacterial pathogens. Cystobactamids, recently discovered natural products from myxobacteria, are an exception to this trend. Their unusual chemical structure, composed of oligomeric para-aminobenzoic acid moieties, is associated with a high antibiotic activity through the inhibition of gyrase. In this study, structural determinants of cystobactamid's antibacterial potency were defined at five positions, which were varied using three different synthetic routes to the cystobactamid scaffold. The potency against Acinetobacter baumannii could be increased ten-fold to an MIC (minimum inhibitory concentration) of 0.06 μg mL−1, and the previously identified spectrum gap of Klebsiella pneumoniae could be closed compared to the natural products (MIC of 0.5 μg mL−1). Proteolytic degradation of cystobactamids by the resistance factor AlbD was prevented by an amide-triazole replacement. Conjugation of cystobactamid's N-terminal tetrapeptide to a Bodipy moiety induced the selective localization of the fluorophore for bacterial imaging purposes. Finally, a first in vivo proof of concept was obtained in an E. coli infection mouse model, where derivative 22 led to the reduction of bacterial loads (cfu, colony-forming units) in muscle, lung and kidneys by five orders of magnitude compared to vehicle-treated mice. These findings qualify cystobactamids as highly promising lead structures against infections caused by Gram-positive and Gram-negative bacterial pathogens.en_US
dc.description.sponsorshipDeutsches Zentrum für Infektionsforschungen_US
dc.language.isoenen_US
dc.publisherRSCen_US
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titleSynthetic studies of cystobactamids as antibiotics and bacterial imaging carriers lead to compounds with high: In vivo efficacyen_US
dc.typeArticleen_US
dc.identifier.eissn20416539
dc.contributor.departmentHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.en_US
dc.identifier.journalChemical Scienceen_US
dc.identifier.eid2-s2.0-85079237979
dc.identifier.scopusidSCOPUS_ID:85079237979
dc.source.volume11
dc.source.issue5
dc.source.beginpage1316
dc.source.endpage1334
refterms.dateFOA2020-11-06T14:53:03Z
dc.source.journaltitleChemical Science


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