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Due to worldwide increasing resistances, there is a considerable need for antibacterial compounds with modes of action not yet realized in commercial antibiotics. One such promising structure is the acetyl-CoA carboxylase (ACC) inhibitor moiramide B which shows strong antibacterial activity against gram-positive bacteria such as Bacillus subtilis and weaker activities against gram-negative bacteria. However, the narrow structure-activity relationship of the pseudopeptide unit of moiramide B represents a formidable challenge for any optimization strategy. In contrast, the lipophilic fatty acid tail is considered an unspecific vehicle responsible only for the transport of moiramide into the bacterial cell. Here we show that the sorbic acid unit, in fact, is highly relevant for ACC inhibition. A hitherto undescribed sub-pocket at the end of the sorbic acid channel binds strongly aromatic rings and allows the development of moiramide derivatives with altered antibacterial profiles including anti-tubercular activity. © 2023 The Authors. ChemMedChem published by Wiley-VCH GmbH.


Irina Kollmorgen, Nathalie Bachmann, Michael Dal Molin, Carsten Degenhart, Eldar Zent, Vikram Pareek, Uwe Koch, Jan Rybniker, Nils Metzler-Nolte, Raphael Stoll, Bert Klebl, Julia Elisabeth Bandow, Jürgen Scherkenbeck. A Reinvestigation of the Role of the Sorbic Acid Tail on the Antibacterial and Anti-Tuberculosis Properties of Moiramide B. ChemMedChem. 2023 Jun 01;18(11):e202200631

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PMID: 36883965

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