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

Luminmycins A–C, Cryptic Natural Products from <i>Photorhabdus luminescens</i> Identified by Heterologous Expression in <i>Escherichia coli</i>

The 18 kb “silent” luminmycin biosynthetic pathway from <i>Photorhabdus luminescens</i> was cloned into a vector by using the newly established linear–linear homologous recombination and successfully expressed in <i>Escherichia coli</i>. Luminmycins A–C (<b>1</b>–<b>3</b>) were isolated from the heterologous host, and their structures were elucidated using 2D NMR spectroscopy and HRESIMS. Luminmycin A is a deoxy derivative of the previously reported glidobactin A, while luminmycins B and C most likely represent its acyclic biosynthetic intermediates. Compound <b>1</b> showed cytotoxicity against the human colon carcinoma HCT-116 cell line with an IC₅₀ value of 91.8 nM, while acyclic <b>2</b> was inactive at concentrations as high as 100 μg/mL

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

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

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

Juniperolide A: A New Polyketide Isolated from a Terrestrial Actinomycete, <i>Streptomyces</i> sp.

A new linear polyketide, juniperolide A (<b>1</b>), was produced by the terrestrial actinomycete (Lv1-48) isolated from the rhizosphere of the plant <i>Juniperus excelsa</i>. The juniperolide A (<b>1</b>) structure contains a THP unit and a 3-amino-2,3,6-trideoxyhexose as the glycosidic moiety. Mosher’s analysis was used for absolute stereochemistry determinations at C-2, C-8, C-20, and C-4′, while the relative stereochemistry assignments of the remaining stereocenters were based on ROESY correlations and <i>J</i>-based coupling

Discovery and Synthesis of Namalide Reveals a New Anabaenopeptin Scaffold and Peptidase Inhibitor

The discovery, structure elucidation, and solid-phase synthesis of namalide, a marine natural product, are described. Namalide is a cyclic tetrapeptide; its macrocycle is formed by only three amino acids, with an exocyclic ureido phenylalanine moiety at its C-terminus. The absolute configuration of namalide was established, and analogs were generated through Fmoc-based solid phase peptide synthesis. We found that only natural namalide and not its analogs containing l-Lys or l-<i>allo</i>-Ile inhibited carboxypeptidase A at submicromolar concentrations. In parallel, an inverse virtual screening approach aimed at identifying protein targets of namalide selected carboxypeptidase A as the third highest scoring hit. Namalide represents a new anabaenopeptin-type scaffold, and its protease inhibitory activity demonstrates that the 13-membered macrolactam can exhibit similar activity as the more common hexapeptides

Combining in Silico and Biophysical Methods for the Development of Pseudomonas aeruginosa Quorum Sensing Inhibitors: An Alternative Approach for Structure-Based Drug Design

The present work deals with the optimization of an inhibitor of PqsD, an enzyme essential for Pseudomonas aeruginosa quorum sensing apparatus. Molecular docking studies, supported by biophysical methods (surface plasmon resonance, isothermal titration calorimetry, saturation transfer difference NMR), were used to illuminate the binding mode of the 5-aryl-ureidothiophene-2-carboxylic acids. Enabled to make profound predictions, structure-based optimization led to increased inhibitory potency. Finally a covalent inhibitor was obtained. Binding to the active site was confirmed by LC-ESI-MS and MALDI-TOF-MS experiments. Following this rational approach, potent PqsD inhibitors were efficiently developed within a short period of time. This example shows that a combination and careful application of in silico and biophysical methods represents a powerful complement to cocrystallography

CrocadepsinsDepsipeptides from the Myxobacterium <i>Chondromyces crocatus</i> Found by a Genome Mining Approach

Analysis of the genome sequence of the myxobacterium <i>Chondromyces crocatus</i> <i>Cm</i> c5 revealed the presence of numerous cryptic megasynthetase gene clusters, one of which we here assign to two previously unknown chlorinated metabolites by a comparative gene inactivation and secondary metabolomics approach. Structure elucidation of these compounds revealed a unique cyclic depsipeptide skeleton featuring β- and δ-amide bonds of aspartic acid and 3-methyl ornithine moieties, respectively. Insights into their biosynthesis were obtained by targeted gene inactivation and feeding experiments employing isotope-labeled precursors. The compounds were produced ubiquitously by the species <i>Chondromyces crocatus</i> and were found to inhibit the carbon storage regulator-RNA interaction

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