Bacterial symbionts and natural products

Abstract

The study of bacterial symbionts of eukaryotic hosts has become a powerful discovery engine for chemistry. This highlight looks at four case studies that exemplify the range of chemistry and biology involved in these symbioses: a bacterial symbiont of a fungus and a marine invertebrate that produce compounds with significant anticancer activity, and bacterial symbionts of insects and nematodes that produce compounds that regulate multilateral symbioses.

Fig. 1

Selected bacterial products that have changed conventional wisdom in both chemistry and biology.

Fig. 2

Natural products produced via modular enzymatic assembly lines. (a) Hypothetical mixed polyketide synthase (blue) and nonribosomal peptide synthetase (red) complex. Polyketide synthases accept and condense short fatty acyl-Coenzyme A (CoA) substrates. Nonribosomal peptide synthetases accept and condense amino acid monomer units at the expense of ATP. Both modular enzymes carry the intermediates via labile thioester attachments. Individual enzyme domains are represented as “balls on a string”. For simplification, the domain functionalities are not shown or discussed. The chain termination event is typically catalyzed by a thioesterase domain. The reader is directed to general reviews on polyketide and nonribosomal peptide biosynthesis.^, (b) Structure of rhizoxin (5). One of the intermediates, 5a, was identified by inactivating the terminal thioesterase domain. Intermediate 5a represents a substrate for the β-branch module, which installs rhizoxin’s δ-lactone via a Michael addition.

Fig. 3

Ribosomally produced cyanobactins. Precursor peptides PatE2 and TruE2 are shown, which can be prenylated, as in the case of the trunkamides (bottom), and heterocyclized in both cases (top and bottom). The final product cassette sequences are boxed. Heterocyclized oxazolines are shown in blue and thiazolines/thiazoles are shown in red. The protease recognition sites surrounding the two cassettes in each precursor peptide are underlined. The specific leader sequences (X_n) are not shown.

Fig. 4

Selected bacterial products from Actinobacteria-insect mutualisms. The antifungals dentigerumycin (10) and mycangimycin (11) both exhibit specificity against the parasitic fungus over the food fungus.

Fig. 5

Bacterial stilbenes and vinyl isocyanide natural products. (a) The stilbene biosynthetic pathway in bacteria is initiated from two amino acid substrates. Phenylalanine is converted to cinnamic acid by a phenylalanine ammonia lyase (StlA), which is converted to its CoA thioester by a CoA ligase (StlB). Leucine is metabolized via the branched chain fatty acid pathway (BkdA/B) and elongated by BkdC. The two advanced substrates are cyclized in a head-to-head fashion by StlC to produce stilbene 12. (b) Vinyl isocyanide biosynthetic genes. IsnA excises the C2 of ribulose-5-phosphate to produce the carboxy indole isocyanide intermediate. IsnB accepts the diffusible IsnA product and catalyzes an oxidative decarboxylation to the final indole vinyl isocyanide product 15. (c) The insect pathogens X. nematophila and P. luminescens both produce the glycoside isocyanide rhabduscin (13, relative configuration). The plant pathogen E. carotovora and an Enterobacter species produce byelyankacin (14).