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6 recordsLinked to original sources
PubMed2026

Discovery of Glycosylated β-Amino Acid-Containing Macrolactams from Nonomuraea sp. 0L2P via Genome Mining.

β-Amino acid-containing macrolactams (β-AACMs) are a class of bioactive natural products characterized by nitrogen-containing starter units within polyketide-derived macrocycles. Here, we report four previously undescribed macrolactams, gruelactams A-D (1-4), from Nonomuraea sp. 0L2P, discovered through an integrated approach combining genome mining, 15N-labeling, and antibacterial screening. Their planar structures were elucidated by comprehensive spectroscopic analyses, including 1D and 2D NMR and HRESI-MS, and their configurations were partially assigned based on ROESY data and bioinformatic analysis. Genome sequencing and antiSMASH analysis identified a putative type I polyketide synthase (PKS) biosynthetic gene cluster, enabling the proposal of a biosynthetic pathway. Bioactivity assays showed that gruelactam D (4) exhibits antibacterial activity against Bacillus cereus and Staphylococcus aureus, with MIC values of 8 and 16 μg/mL, respectively. These findings expand the chemical diversity of β-AACMs and demonstrate the utility of genome-guided approaches for discovering bioactive natural products from rare actinomycetes.

Anti-Bacterial Agents↗
PubMed2026

Feasibility and Efficacy of Lorlatinib in Japanese Patients With Relapsed/Refractory ALK-Aberrant Neuroblastoma.

Lorlatinib, a third-generation ALK inhibitor, was administered off-label to five heavily pretreated patients with relapsed or refractory ALK-aberrant neuroblastoma. ALK alterations included F1174L, R1275Q, BEND5::ALK fusion, and ALK amplification; three patients had MYCN amplification. Best responses were three partial responses and two disease progressions. The longest progression-free survival (6.7 months) occurred in a patient with F1174L and non-amplified MYCN, whereas rapid progression was observed in two MYCN-amplified cases. Lorlatinib was generally well tolerated with manageable adverse events. These findings suggest that lorlatinib is a feasible therapeutic option in ALK-aberrant neuroblastoma and that clinical heterogeneity in treatment response warrants further investigation.

Humans↗
PubMed1978

Study of ansamycin inhibition of a ribonucleic acid-directed deoxyribonucleic acid polymerase by an immobilized template assay.

A series of structurally related ansamycins have been analyzed, in a new immobilized template assay, to determine the mechanism by which they inhibit a ribonucleic acid-directed deoxyribonucleic acid (DNA) polymerase from Moloney murine leukemia virus. By this assay, we can better correlate specific structures of these drugs with inhibitory mechanisms. Using an immobilized template, we were also able to observe drug effects on the stability of complexes formed between the polymerase, a template (polyadenylic acid-agarose), and a primer, as well as to monitor the synthesis of DNA in the presence of drug. For each drug, we determined the complex (intermediate in DNA synthesis) which was primarily affected and whether the effect was due to a destabilization process. Although the activity and specificity of the unsubstituted ansamycins (streptovaricins and rifamycin SV) were modulated by conformation of the molecule and electron density of the aromatic ring, the principal mode of inhibition is, apparently, drug binding to a polymerase-template complex; the drug binds in a manner which prevents subsequent formation of a polymerase-template-primer complex. However, some derivatives of rifamycin SV, when substituted at carbon-3 with bulky or hydrophobic side chains, displayed markedly different modes of action. For example, demethyl dimethyl rifampin prevented the formation of polymerase-template complexes, whereas rifazacyclo 16 acted by promoting the dissociation of polymerase-template-primer complexes.

Anti-Bacterial Agents↗
PubMed1979

Early intermediates in the biosynthesis of ansamycins. II. Isolation and identification of proansamycin B-M1 and protorifamycin i-M1.

Proansamycin B-M1 and protorifamycin I-M1 were isolated as minor compounds from fermentations of the protorifamycin I producing strain Nocardia mediterranei F 1/24, identified by means of chemical and spectroscopic methods and shown to be degradation products of the hypothetical proansamycin B postulated in part I of this series of papers and of protorifamycin I, respectively.

Anti-Bacterial Agents↗