A Reinvestigation of the Role of the Sorbic Acid Tail on the Antibacterial and Anti‐Tuberculosis Properties of Moiramide B

Author:

Kollmorgen Irina1,Bachmann Nathalie2,Dal Molin Michael34,Degenhart Carsten4,Zent Eldar4,Pareek Vikram2,Koch Uwe4,Rybniker Jan345,Metzler‐Nolte Nils6,Stoll Raphael7,Klebl Bert4,Bandow Julia Elisabeth2,Scherkenbeck Jürgen1ORCID

Affiliation:

1. School of Mathematics and Natural Sciences Department of Chemistry and Biology University of Wuppertal Gaussstrasse 20 42119 Wuppertal Germany

2. Faculty of Biology and Biotechnology Ruhr University Bochum Universitätsstrasse 150 44780 Bochum Germany

3. Faculty of Medicine University of Cologne Cologne Germany

4. Lead Discovery Center GmbH Otto-Hahn-Strasse 15 44227 Dortmund Germany

5. German Center for Infection Research (DZIF) Partner Site Bonn-Cologne Cologne Germany

6. Faculty of Chemistry and Biochemistry Inorganic Chemistry I – Bioinorganic Chemistry Ruhr University Bochum Universitätsstrasse 150 44780 Bochum Germany

7. Faculty of Chemistry and Biochemistry Biomolecular Spectroscopy and RUBiospec|NMR Ruhr University Bochum Universitätsstrasse 150 44780 Bochum Germany

Abstract

AbstractDue 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.

Publisher

Wiley

Subject

Organic Chemistry,General Pharmacology, Toxicology and Pharmaceutics,Molecular Medicine,Drug Discovery,Biochemistry,Pharmacology

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