Borrelidin B: Isolation, Biological Activity, and Implications for Nitrile Biosynthesis

Abstract

Borrelidin (1) is a nitrile-containing bacterially derived polyketide that is a potent inhibitor of bacterial and eukaryotic threonyl-tRNA synthetases. We now report the discovery of borrelidin B (2), a tetrahydro-borrelidin derivative containing an aminomethyl group in place of the nitrile functionality in borrelidin. The discovery of this new metabolite has implications for both the biosynthesis of the nitrile group and the bioactivity of the borrelidin compound class. Screening in the SToPS assay for tRNA synthetase inhibition revealed that the nitrile moiety is essential for activity, while profiling using our in-house image-based cytological profiling assay demonstrated that 2 retains biological activity by causing a mitotic stall, even in the absence of the nitrile motif.

Unrivalled diversity: the many roles and reactions of bacterial cytochromes P450 in secondary metabolism

“…One example in which a highly complex biosynthetic pathways intersects with such a P450-mediated transformation is found in borrelidin (BorI) biosynthesis: 162 BorI is implicated in the formation of a nitrile group found within borrelidin, and whilst transformations have been reported in which a carboxylic acid is directly converted into a nitrile group, 163 this appears not to be the case in borrelidin biosynthesis, where gene disruption studies indicate that BorI only affords acid products via a shunt pathway. Mechanistic alternatives postulated include both alcohol 164 and aldehyde 162 intermediates playing a role in nitrile formation together with other biosynthetic enzymes, although to date the exact pathway by which the nitrile moiety is installed remains unclear. Thiotetronate biosynthesis (mixed PKS/NRPS), specically thiotetroamide C, 165 also utilises a P450 (TtmP) to generate a carboxylic acid moiety from a methyl group, although in this case the acid group is further converted into a primary amide via the actions of the amidotransferase TtmN that consumes both ATP and glutamine to perform this reaction.…”

A Single Enzyme Transforms a Carboxylic Acid into a Nitrile through an Amide Intermediate

“…[1] Though these are increasingly being recognized as important next generation antibiotics and cytotoxic agents with pharmaceutical potential, [2,3] the biosynthesis of these compounds is very poorly understood. Only one biosynthetic route utilizing at least three separate enzymes has previously been described with mechanistic detail involving aldoxime formation [4] and a subsequent dehydration [5,6] (Figure 1).…”

Borrelidins C–E: New Antibacterial Macrolides from a Saltern-Derived Halophilic Nocardiopsis sp.

“…in the early days of antibiotic discovery in 1949 [9], only one additional member, borrelidin B, in which the nitrile functional group was reduced to a primary amine, has been reported, and this member was isolated from a marine sediment-derived Streptomyces sp. in 2014 [14]. The discovery of borrelidins C–E as the first secondary metabolites from a saltern-derived rare actinomycete genus Nocardiposis emphasizes the unexplored potential of halophilic rare actinomycetes inhabiting extremely saline saltern environments.…”