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

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.