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

Abstract

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) inhibi-tor moiramide B which shows strong antibacterial activity against gram-positive bacteria such asBacillus subtilisand 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 opti-mization strategy.​In contrast, the lipophilic fatty acid tail is considered an unspe-cific vehicle responsible only for the transport of moiramide into the bac-terial 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 andallows the development of moiramide derivatives with altered antibacterial profiles including anti-tubercular activity.