Dilarmycins A–C, Calcium-Dependent Lipopeptide Antibiotics with a Non-canonical Ca²⁺-Binding Motif

Genome analysis of strain Streptomyces sp. CA-278952 revealed a biosynthetic gene cluster encoding a putative lipopeptide with a sequence containing an Asp-Gly-Glu-Ala motif. We envisioned that this motif could mimic the canonical Asp-X-Asp-Gly sequence found in previously reported calcium-dependent lipopeptide antibiotics. Chemical investigation of the producing strain led to the discovery of three novel lipodepsipeptides, dilarmycins A–C. The calcium-dependent antibacterial activity of the new compounds was confirmed against the Gram-positive pathogens methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus

Dilarmycins A–C, Calcium-Dependent Lipopeptide Antibiotics with a Non-canonical Ca²⁺-Binding Motif

Genome analysis of strain Streptomyces sp. CA-278952 revealed a biosynthetic gene cluster encoding a putative lipopeptide with a sequence containing an Asp-Gly-Glu-Ala motif. We envisioned that this motif could mimic the canonical Asp-X-Asp-Gly sequence found in previously reported calcium-dependent lipopeptide antibiotics. Chemical investigation of the producing strain led to the discovery of three novel lipodepsipeptides, dilarmycins A–C. The calcium-dependent antibacterial activity of the new compounds was confirmed against the Gram-positive pathogens methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus

Non-geminal Aliphatic Dihalogenation Pattern in Dichlorinated Diaporthins from <i>Hamigera fusca</i> NRRL 35721

Two new epimeric dihalogenated diaporthins, (9<i>R</i>^<i>*</i>)-8-methyl-9,11-dichlorodiaporthin (<b>2</b>) and (9<i>S</i>^<i>*</i>)-8-methyl-9,11-dichlorodiaporthin (<b>3</b>), have been isolated from the soil fungus <i>Hamigera fusca</i> NRRL 35721 alongside the known regioisomeric isocoumarin 8-methyl-11,11-dichlorodiaporthin (<b>1</b>). Their structures were elucidated by high-resolution mass spectrometry and NMR spectroscopy combined with molecular modeling. Compounds <b>1</b>–<b>3</b> are the first isocoumarins and the first halogenated metabolites ever reported from the <i>Hamigera</i> genus. The new compounds <b>2</b> and <b>3</b> display a non-geminal aliphatic dichlorination pattern unprecedented among known fungal dihalogenated aromatic polyketides. A bifunctional methyltransferase/aliphatic halogenase flavoenzyme is proposed to be involved in the biosynthesis of dichlorinated diaporthins <b>1</b>–<b>3</b>. These metabolites are weakly cytotoxic

MDN-0185, an Antiplasmodial Polycyclic Xanthone Isolated from <i>Micromonospora</i> sp. CA-256353

A potent antiplasmodial polycyclic xanthone, MDN-0185 (<b>1</b>), was isolated from an unidentified species of the genus <i>Micromonospora</i>. The planar structure of <b>1</b> was established as a seven-ring polycyclic xanthone with partial structures very similar to two known natural products, namely, xantholipin and Sch 54445. Using ROESY correlations, the relative stereochemistry of the two independent stereoclusters of compound <b>1</b> could be determined. Mosher analysis and comparison of the specific rotation of compound <b>1</b> with that of xantholipin allowed the determination of its absolute configuration. Compound <b>1</b> exhibited an IC₅₀ of 9 nM against <i>Plasmodium falciparum</i> 3D7 parasites

MDN-0104, an Antiplasmodial Betaine Lipid from <i>Heterospora chenopodii</i>

Bioassay-guided fractionation of the crude fermentation extract of <i>Heterospora chenopodii</i> led to the isolation of a novel monoacylglyceryltrimethylhomoserine (<b>1</b>). The structure of this new betaine lipid was elucidated by detailed spectroscopic analysis using one- and two-dimensional NMR experiments and high-resolution mass spectrometry. Compound <b>1</b> displayed moderate <i>in vitro</i> antimalarial activity against <i>Plasmodium falciparum</i>, with an IC₅₀ value of 7 μM. This betaine lipid is the first monoacylglyceryl­trimethyl­homoserine ever reported in the Fungi, and its acyl moiety also represents a novel natural 3-keto fatty acid. The new compound was isolated during a drug discovery program aimed at the identification of new antimalarial leads from a natural product library of microbial extracts. Interestingly, the related fungus <i>Heterospora dimorphospora</i> was also found to produce compound <b>1</b>, suggesting that species of this genus may be a promising source of monoacylglyceryltrimethylhomoserines

Branimycins B and C, Antibiotics Produced by the Abyssal Actinobacterium <i>Pseudonocardia carboxydivorans</i> M‑227

Two new antibiotics, branimycins B (<b>2</b>) and C (<b>3</b>), were produced by fermentation of the abyssal actinobacterium <i>Pseudonocardia carboxydivorans</i> M-227, isolated from deep seawater of the Avilés submarine Canyon. Their structures were elucidated by HRMS and NMR analyses. These compounds exhibit antibacterial activities against a panel of Gram-positive bacteria, including <i>Corynebacterium urealyticum</i>, <i>Clostridium perfringens</i>, and <i>Micrococcus luteus</i>, and against the Gram-negative bacterium <i>Neisseria meningitidis.</i> Additionally, branimycin B displayed moderate antibacterial activity against other Gram-negative bacteria such as <i>Bacteroides fragilis</i>, <i>Haemophilus influenzae</i>, and <i>Escherichia coli</i>, and branimycin C against the Gram-positive <i>Enterococcus faecalis</i> and methicillin-sensitive and methicillin-resistant <i>Staphylococcus aureus.</i

Lasionectrin, a Naphthopyrone from a <i>Lasionectria</i> sp.

A new naphthopyrone derivative, lasionectrin (<b>1</b>), was isolated from fermentations of an <i>Acremonium</i>-like fungus provisionally identified as a <i>Lasionectria</i> sp. (Ascomycota, Hypocreales) and isolated from forest leaf litter from Equatorial Guinea. Its structure was determined by a combination of spectroscopic techniques, including UV, (+)-HRESIMS, and 1D and 2D NMR spectroscopy, and comparison with published data for related fungal metabolites. Compound <b>1</b> inhibited the growth of <i>Plasmodium falciparum</i> with an IC₅₀ value of 11 μM

Isolation and Structural Elucidation of Cyclic Tetrapeptides from <i>Onychocola sclerotica</i>

Three new cyclic tetrapeptides (<b>1</b>–<b>3</b>) have been isolated from the crude fermentation extract of <i>Onychocola sclerotica</i>. The planar structures of <b>1</b>–<b>3</b> were elucidated by detailed spectroscopic analyses using one- and two-dimensional NMR experiments and high-resolution mass spectrometry. The absolute configuration of the amino acid residues in each cyclotetrapeptide was established by Marfey’s method. Compounds <b>1</b>–<b>3</b> displayed activity as cardiac calcium channel blockers (Cav1.2) but did not inhibit the hERG potassium channel and were not cytotoxic. These peptides are the first secondary metabolites ever reported from fungi of the order Arachnomycetales