Biosynthesis of the Antibiotic Nematophin and Its Elongated Derivatives in Entomopathogenic Bacteria

Abstract

Nematophin, a known antibiotic natural product against Staphylococcus aureus for almost 20 years, is produced by all strains of Xenorhabdus nematophila. Despite its simple structure, its biosynthesis was unknown. Its biosynthetic pathway is reported using heterologous production in Escherichia coli. Additionally, the identification, structure elucidation, and biosynthesis of six extended nematophin derivatives from Xenorhabdus PB62.4 carrying an additional valine are reported. Preliminary bioactivity studies suggest a biological role of these compounds in the bacteria-nematode-insect symbiosis.

Bacterial pathogens: threat or treat (a review on bioactive natural products from bacterial pathogens)

“…The PEA analogues are produced in minor amounts, implying that the substrate preference of the C term domain in RdpD is likely tryptamine over phenylethylamine. 131 A similar BGC was identied in Xenorhabdus PB62.4 containing two monomodular NRPS, Pb62A resembling RdpD with a broken C starter domain, and Pb62B like the RXP RdpC terminal module with a complete C domain. Heterologous expression of the pb62 gene cluster in E. coli fed with either PEA or TRA has permitted to unlock the production of new elongated nematophin derivatives containing an additional valine motif in the structure which was assigned the name nevaltophins 26a-f.…”

“…131 The biosynthesis of nematophin is proposed to originate from the monomodular NRPS, RdpD, which is closely related to the RXP-producing NRPS, RdpABC but differs in the incorporation of a-keto carboxylic acid as the starting unit. 131 Heterologous expression of the rdpD gene from X. nematophila ATCC 19601 strain in Escherichia coli fed with either phenylethylamine (PEA) or tryptamine (TRA), resulted in the production of new nematophin congeners, 18b-d (Fig. 8A).…”

“…In contrast, the wild type (WT) X. nematophila strain only produced nematophin 18a even when fed with PEA or TRA and the presence of the amine compounds did not enhance its production level. 131 Very few non-ribosomal peptides containing a-keto acid building blocks have been described to date. 131,132 The a-keto acid precursors in nonribosomal cereulide from Bacillus cereus and valinomycin from Streptomyces spp.…”

“…131 Very few non-ribosomal peptides containing a-keto acid building blocks have been described to date. 131,132 The a-keto acid precursors in nonribosomal cereulide from Bacillus cereus and valinomycin from Streptomyces spp. occur via deamination of a-amino acids such as valine, isoleucine or alanine.…”

Effects of cpxR on the growth characteristics and antibiotic production of Xenorhabdus nematophila

“…It displays strong antifungal and antibacterial activities (Li et al, 1997;Kennedy et al, 2000). A monomodular non-ribosomal peptide synthetase (NRPS), RdpD, is responsible for the biosynthesis of nematophin (Cai et al, 2017). Xenocoumacins, including Xcn1 and Xcn2, are the principal antimicrobial compounds secreted by X. nematophila.…”