Cystochromones, Unusual Chromone-Containing Polyketides from the Myxobacterium <i>Cystobacter</i> sp. MCy9104

Seven new chromone-containing polyketides, termed cystochromones A–G, were isolated from the myxobacterial strain <i>Cystobacter</i> sp. MCy9104. Their structures were elucidated using comprehensive NMR spectroscopy and HR-MS/MS. Cystochromones bear a pentadecyl moiety unusually attached at C-5 of the chromone ring. Moreover, isotope-labeled substrate feeding experiments and NMR analysis suggested a hybrid iso-fatty acid and polyketide synthase biosynthetic pathway for these secondary metabolites

Jahnellamides, α‑Keto-β-Methionine-Containing Peptides from the Terrestrial Myxobacterium <i>Jahnella</i> sp.: Structure and Biosynthesis

Two new cyclic peptides, termed jahnellamides A and B, were isolated from the myxobacterium <i>Jahnella</i> sp. Their structures were solved by NMR, ESIMS, and chemical derivatizations. Jahnellamides are a new class of α-ketoamide-containing peptides comprised of nonproteinogenic amino acids, including α-keto-β-methionine and 4-hydroxyglutamic acid. Moreover, <i>in silico</i> analysis of the genome sequence along with feeding experiments allowed us to identify and annotate a candidate nonribosomal peptide synthetase biosynthetic gene cluster containing a polyketide synthase module involved in the formation of the α-ketoamide moiety

Cystomanamides: Structure and Biosynthetic Pathway of a Family of Glycosylated Lipopeptides from Myxobacteria

Cystomanamides A–D were isolated as novel natural product scaffolds from <i>Cystobacter fuscus</i> MCy9118, and their structures were established by spectroscopic techniques including 2D NMR, LC-SPE-NMR/-MS, and HR-MS. The cystomanamides contain β-hydroxy amino acids along with 3-amino-9-methyldecanoic acid that is <i>N</i>-glycosylated in cystomanamide C and D. The gene cluster for cystomanamide biosynthesis was identified by gene disruption as PKS/NRPS hybrid incorporating an iso-fatty acid as starter unit and including a reductive amination step at the interface of the PKS and NRPS modules

Microsclerodermins from Terrestrial Myxobacteria: An Intriguing Biosynthesis Likely Connected to a Sponge Symbiont

The microsclerodermins are unusual peptide natural products exhibiting potent antifungal activity reported from marine sponges of the genera Microscleroderma and Theonella. We here describe a variety of microbial producers of microsclerodermins and pedeins among myxobacteria along with the isolation of several new derivatives. A retrobiosynthetic approach led to the identification of microsclerodermin biosynthetic gene clusters in genomes of Sorangium and Jahnella species, allowing for the first time insights into the intriguing hybrid PKS/NRPS machinery required for microsclerodermin formation. This study reveals the biosynthesis of a “marine natural product” in a terrestrial myxobacterium where even the identical structure is available from both sources. Thus, the newly identified terrestrial producers provide access to additional chemical diversity; moreover, they are clearly more amenable to production optimization and genetic modification than the original source from the marine habitat. As sponge metagenome data strongly suggest the presence of associated myxobacteria, our findings underpin the recent notion that many previously described “sponge metabolites” might in fact originate from such microbial symbionts

Hyalachelins A–C, Unusual Siderophores Isolated from the Terrestrial Myxobacterium <i>Hyalangium minutum</i>

Three new siderophores, termed hyalachelins A–C (<b>1</b>–<b>3</b>), were isolated from the terrestrial myxobacterium <i>Hyalangium minutum</i>. Their structures were determined by 2D NMR and HR-MS/MS experiments, and their stereochemical configuration was established by a combination of NMR data, quantum mechanical calculations, and circular dichroism experiments. Hyalachelins are unusual catecholate-type siderophores that bear a 3,7,8-trihydroxy-1-oxo-1,2,3,4-tetra­hydro­isoquinoline-3-carbox­ylic acid. Their iron chelating activities were evaluated in a CAS assay showing EC₅₀ values of ∼30 μM

Aetheramides A and B, Potent HIV-Inhibitory Depsipeptides from a Myxobacterium of the New Genus “<i>Aetherobacter</i>”

Aetheramides are structurally distinctive cyclic peptides isolated from a novel myxobacterial genus proposed to be termed “<i>Aetherobacter”</i>. The structures were solved by a combination of NMR analyses, quantum mechanical calculations, and chemical derivatizations. Aetheramides which contain a unique polyketide moiety and two amino acid residues potently inhibited HIV-1 infection with IC₅₀ values of ∼0.015 μM. Furthermore aetheramides showed cytostatic activity against human colon carcinoma (HCT-116) cells with IC₅₀ values of 0.11 μM

Discovery and Characterization of a Myxobacterial Lanthipeptide with Unique Biosynthetic Features and Anti-inflammatory Activity

The genomes of myxobacteria harbor a variety of biosynthetic gene clusters encoding numerous secondary metabolites, including ribosomally synthesized and post-translationally modified peptides (RiPPs) with diverse chemical structures and biological activities. However, the biosynthetic potential of RiPPs from myxobacteria remains barely explored. Herein, we report a novel myxobacteria lanthipeptide myxococin identified from Myxococcus fulvus. Myxococins represent the first example of lanthipeptides, of which the characteristic multiple thioether rings are installed by employing a Class II lanthipeptide synthetase MfuM and a Class I lanthipeptide cyclase MfuC in a cascaded way. Unprecedentedly, we biochemically characterized the first M61 family aminopeptidase MfuP involved in RiPP biosynthesis, demonstrating that MfuP showed the activity of an endopeptidase activity. MfuP is leader-independent but strictly selective for the multibridge structure of myxococin A and responsible for unwrapping two rings via amide bond hydrolysis, yielding myxococin B. Furthermore, the X-ray crystal structure of MfuP and structural analysis, including active-site mutations, are reported. Finally, myxococins are evaluated to exhibit anti-inflammatory activity in lipopolysaccharide-induced macrophages without detectable cytotoxicity