Cystobactamid 507 : Concise Synthesis, Mode of Action, and Optimization toward More Potent Antibiotics

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dc.identifier.uri Elgaher, Walid A.M. Hamed, Mostafa M. Baumann, Sascha Herrmann, Jennifer Siebenbürger, Lorenz Krull, Jana Cirnski, Katarina Kirschning, Andreas Müller, Rolf Hartmann, Rolf W. 2021-04-30T05:23:10Z 2021-04-30T05:23:10Z 2020
dc.identifier.citation Elgaher, W.A.M.; Hamed, M.M.; Baumann, S.; Herrmann, J.; Siebenbürger, L.; et al.: Cystobactamid 507 : Concise Synthesis, Mode of Action, and Optimization toward More Potent Antibiotics. In: Chemistry - A European Journal 26 (2020), Nr. 32, S. 7219-7225. DOI:
dc.description.abstract Lack of new antibiotics and increasing antimicrobial resistance are among the main concerns of healthcare communities nowadays, and these concerns necessitate the search for novel antibacterial agents. Recently, we discovered the cystobactamids—a novel natural class of antibiotics with broad-spectrum antibacterial activity. In this work, we describe 1) a concise total synthesis of cystobactamid 507, 2) the identification of the bioactive conformation using noncovalently bonded rigid analogues, and 3) the first structure–activity relationship (SAR) study for cystobactamid 507 leading to new analogues with high metabolic stability, superior topoisomerase IIA inhibition, antibacterial activity and, importantly, stability toward the resistant factor AlbD. Deeper insight into the mode of action revealed that the cystobactamids employ DNA minor-groove binding as part of the drug–target interaction without showing significant intercalation. By designing a new analogue of cystobactamid 919-2, we finally demonstrated that these findings could be further exploited to obtain more potent hexapeptides against Gram-negative bacteria. © 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. eng
dc.language.iso eng
dc.publisher Weinheim : Wiley-VCH
dc.relation.ispartofseries Chemistry - A European Journal 26 (2020), Nr. 32
dc.rights CC BY 4.0 Unported
dc.subject antimicrobial agents eng
dc.subject bacteria eng
dc.subject anti-bacterial activity eng
dc.subject antimicrobial resistances eng
dc.subject bioactive conformation eng
dc.subject concise synthesis eng
dc.subject gram-negative bacteria eng
dc.subject metabolic stability eng
dc.subject topoisomerase iia eng
dc.subject total synthesis eng
dc.subject antibiotics eng
dc.subject.ddc 540 | Chemie ger
dc.subject.ddc 660 | Technische Chemie ger
dc.title Cystobactamid 507 : Concise Synthesis, Mode of Action, and Optimization toward More Potent Antibiotics
dc.type Article
dc.type Text
dc.relation.essn 1521-3765
dc.relation.issn 0947-6539
dc.bibliographicCitation.issue 32
dc.bibliographicCitation.volume 26
dc.bibliographicCitation.firstPage 7219
dc.bibliographicCitation.lastPage 7225
dc.description.version publishedVersion
tib.accessRights frei zug�nglich

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