Salimabromide: Unexpected Chemistry from the Obligate Marine Myxobacterium Enhygromxya salina

Marine myxobacteria (Enhygromyxa, Plesiocystis, Pseudoenhygromyxa, Haliangium) are phylogenetically distant from their terrestrial counterparts. Salimabromide is the first natural product from the Plesiocystis/Enhygromyxa clade of obligatory marine myxobacteria. Salimabromide has a new tetracyclic carbon skeleton, comprising a brominated benzene ring, a furano lactone residue, and a cyclohexane ring, bridged by a seven‐membered cyclic moiety. The absolute configuration was deduced from experimental and calculated CD data. Salimabromide revealed antibiotic activity towards Arthrobacter cristallopoietes.     

Disciformycins A and B: 12‐Membered Macrolide Glycoside Antibiotics from the Myxobacterium Pyxidicoccus fallax Active against Multiresistant Staphylococci

Two macrolide glycosides with a unique scaffold were isolated from cultures of the myxobacterium Pyxidicoccus fallax. Their structures, including absolute configurations, were elucidated by a combination of NMR, MS, degradation, and molecular modeling techniques. Analysis of the proposed biosynthetic gene cluster led to insights into the biosynthesis of the polyketide and confirmed the structure assignment. The more active compound, disciformycin B, potently inhibits methicillin‐ and vancomycin‐resistant Staphylococcus aureus.     

Pyrrole aminoimidazole alkaloid metabiosynthesis with marine sponges Agelas conifera and Stylissa caribica

Game-SET-match: Pyrrole aminoimidazole alkaloids (PAIs) are metabiosynthesized from chlorinated analogues of oroidin by cell-free enzyme preparations from PAI-producing sponges. Evidence and implications for the biosynthesis of PAIs include putative single-electron transfers (SETs) that promote C-C bond-forming reactions of precursors.     

A Long-Range Acting Dehydratase Domain as the Missing Link for C17-Dehydration in Iso-Migrastatin Biosynthesis

The dehydratase domains (DHs) of the iso-migrastatin (iso-MGS) polyketide synthase (PKS) were investigated by systematic inactivation of the DHs in module-6, -9, -10 of MgsF (i.e., DH6, DH9, DH10) and module-11 of MgsG (i.e., DH11) in vivo, followed by structural characterization of the metabolites accumulated by the mutants, and biochemical characterization of DH10 in vitro, using polyketide substrate mimics with varying chain lengths. These studies allowed us to assign the functions for all four DHs, identifying DH10 as the dedicated dehydratase that catalyzes the dehydration of the C17 hydroxy group during iso-MGS biosynthesis. In contrast to canonical DHs that catalyze dehydration of the β-hydroxy groups of the nascent polyketide intermediates, DH10 acts in a long-range manner that is unprecedented for type I PKSs, a novel dehydration mechanism that could be exploited for polyketide structural diversity by combinatorial biosynthesis and synthetic biology.     

Structure and Biosynthetic Assembly of Gulmirecins,Macrolide Antibiotics from the Predatory Bacterium Pyxidicoccus fallax

The gulmirecins constitute a new class of glycosylated macrolides that were isolated from the predatory bacterium Pyxidicoccus fallax HKI 727. Their structures were solved by a combination of NMR spectroscopic experiments and chemical derivatization. Analysis of the annotated gulmirecin gene cluster complemented the configurational assignment and provided insights into the stereochemical course of the biosynthetic assembly. The gulmirecins exhibit strong activity against staphylococci, including methicillin‐resistant Staphylococcus aureus, but no cytotoxic effects on human cells.     

Iterative Assembly of Two Separate Polyketide Chains by the Same Single‐Module Bacterial Polyketide Synthase in the Biosynthesis of HSAF

Antifungal HSAF (heat‐stable antifungal factor, dihydromaltophilin) is a polycyclic tetramate macrolactam from the biocontrol agent Lysobacter enzymogenes. Its biosynthetic gene cluster contains only a single‐module polyketide synthase–nonribosomal peptide synthetase (PKS‐NRPS), although two separate hexaketide chains are required to assemble the skeleton. To address the unusual biosynthetic mechanism, we expressed the biosynthetic genes in two “clean” strains of Streptomyces and showed the production of HSAF analogues and a polyene tetramate intermediate. We then expressed the PKS module in Escherichia coli and purified the enzyme. Upon incubation of the enzyme with acyl‐coenzyme A and reduced nicotinamide adenine dinucleotide phosphate (NADPH), a polyene was detected in the tryptic acyl carrier protein (ACP). Finally, we incubated the polyene–PKS with the NRPS module in the presence of ornithine and adenosine triphosphate (ATP), and we detected the same polyene tetramate as that in Streptomyces transformed with the PKS‐NRPS alone. Together, our results provide evidence for an unusual iterative biosynthetic mechanism for bacterial polyketide–peptide natural products.