New Nocobactin Derivatives with Antimuscarinic Activity, Terpenibactins A-C, Revealed by Genome Mining of Nocardia terpenica IFM 0406

Abstract

We report a genomics-guided exploration of the metabolic potential of the brasilicardin producer strain Nocardia terpenica IFM 0406. Bioinformatics analysis of the whole genome sequence revealed the presence of a biosynthetic gene cluster presumably responsible for the generation of formerly unknown nocobactin derivatives. Mass spectrometry-assisted isolation led to the identification of three new siderophores, terpenibactins A (1), B (2) and C (3), which belong to the class of nocobactins. Their structures were elucidated by employing spectroscopic techniques. Compounds 1-3 demonstrated inhibitory activity towards the muscarinic M3 receptor, while exhibiting only a low cytotoxicity.

Figure 1

Comparison of the biosynthetic gene clusters encoding (top) nocobactin NA and (bottom) novel terpenibactins.

Figure 2

Detailed view of PKS (orange boxes) and NRPS (green boxes) modules in the terpenibactin gene cluster of N. terpenica IFM 0406, including A domain substrate specificities.

Figure 3

¹H,¹H COSY and ¹H,¹³C HSQC‐TOCSY (bold lines), selected ¹H,¹³C long‐range (red arrows) and selected ¹H,¹H NOESY (dashed blue lines) correlations for terpenibactin A (1). HMFA: hydroxymethyl fatty acid.

Figure 4

Chemical structures of terpenibactins A−C.