Expanding the Myxochelin Natural Product Family by Nicotinic Acid Containing Congeners

Abstract

Myxobacteria represent a viable source of chemically diverse and biologically active secondary metabolites. The myxochelins are a well-studied family of catecholate-type siderophores produced by various myxobacterial strains. Here, we report the discovery, isolation, and structure elucidation of three new myxochelins N1–N3 from the terrestrial myxobacterium Corallococcus sp. MCy9049, featuring an unusual nicotinic acid moiety. Precursor-directed biosynthesis (PDB) experiments and total synthesis were performed in order to confirm structures, improve access to pure compounds for bioactivity testing, and to devise a biosynthesis proposal. The combined evaluation of metabolome and genome data covering myxobacteria supports the notion that the new myxochelin congeners reported here are in fact frequent side products of the known myxochelin A biosynthetic pathway in myxobacteria.

Discovery, Biosynthesis and Biological Activity of a Succinylated Myxochelin from the Myxobacterial strain MSr12020

“…Thus 1 was elucidated as myxochelin-B-succinate based on the similarities with the previously reported siderophore 2. The negative optical rotation and the positive cotton effect observed for 1 (Figure S12) was similar to those observed in naturally occurring and synthetic 2 and 3 -(2S)-isomer [16,17,24,28,41].…”

“…2600 myxobacterial strains [38]. The chosen parameters to evaluate those MS datasets considering the exact mass (exact mass deviation below 5 ppm), isotope pattern, and retention time matching (retention time deviation below 0.3 min) was adapted from a previous study investigating the presence of myxochelin congeners featuring nicotinic acid moieties [17]. This metabolomic survey revealed, that 1 is a commonly observed byproduct of myxochelin B biosynthesis (Figure S14).…”

“…Myxobacteria do not only display exceptional biological characteristics such as a complex chemical communication systems, multicellular development stages and the capability to move in coordinated manner to prey on other microorganisms [11] but are also producers of chemically exceptional and bioactive secondary metabolites [12]. Two different chemical types of siderophores are known to date from myxobacteria: the hydroxamate-type nannochelins [13] and the catecholate-type hyalachelins [14] and myxochelins [15,16], of which the latter have been investigated thoroughly in the last three decades [17][18][19].…”

“…TP-A0861 [24] and Steptomyces albicus m-9-20 [25] or the Chloroflexi bacterium Herpetosiphon aurantiacus [26]. Recently a number of new myxochelin derivatives have been isolated from different myxobacterial strains in which the common 2,3-dihydroxybenzoic acid has been replaced by a nicotinic acid moiety [17] or a 4,5-dihydroimidazole moiety [27]. Due to the relative simple structure of the myxochelins, chemical synthetic efforts led not only to the diversification of the aromatic scaffold [17,28] but also to the generation of hexadentate siderophores termed myxochelin C-F [16].…”

“…Recently a number of new myxochelin derivatives have been isolated from different myxobacterial strains in which the common 2,3-dihydroxybenzoic acid has been replaced by a nicotinic acid moiety [17] or a 4,5-dihydroimidazole moiety [27]. Due to the relative simple structure of the myxochelins, chemical synthetic efforts led not only to the diversification of the aromatic scaffold [17,28] but also to the generation of hexadentate siderophores termed myxochelin C-F [16]. In addition, more myxochelin derivatives have been generated biotechnologically by precursor-directed biosynthesis [29].…”