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) 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.

A Review of Antibacterial Candidates with New Modes of Action

“…130 Recent work has suggested that the sorbamide group in 25 and analogs with aromatic acyl tails can enhance enzyme binding, as well as demonstrating activity against Mycobacterium. 131 The outer membranes of G−ve bacteria contain an asymmetrical bilayer of LPS on the outside and phospholipids on the inside. The biosynthetic pathway for the lipid A portion of LPS is essential and conserved in most G−ve bacteria but is absent in humans, making it an attractive target for antimicrobial intervention 132,133 The lipid A biosynthesis pathway includes a range of targets, such as LpxC (uridine diphosphate-3-O-(hydroxymyristoyl)-N-acetylglucosamine deacetylase), 134 LpxA (UDP-N-acetylglucosamine acyltransferase), 135−137 LpxD (acyl-ACP-dependent N-acyltransferase), 135,138,139 and LpxH (UDP-2,3-diacylglucosamine pyrophosphate hydrolase).…”

“…Both 24 and 25 have broad spectrum low μM minimum inhibitory concentrations (MICs) against pathogens such as S. aureus , S. pneumoniae , E. coli , and P. aeruginosa . , In 2004, it was shown that 24 , 25 , and synthetic analogs inhibited the carboxyltransferase subunit (β-subunit) of the bacterial enzyme acetyl-CoA carboxylase (ACC) with nM affinity. − In 2016, an X-ray crystal structure of moiramide B ( 25 ) bound S. aureus carboxyltransferase showed that the valine-methyl pyrrolidinedione subunit interacted with the enzyme oxyanion holes via an enol form, which mimics the enolate present in biotin . Recent work has suggested that the sorbamide group in 25 and analogs with aromatic acyl tails can enhance enzyme binding, as well as demonstrating activity against Mycobacterium …”