PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Motif discovery”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

22 records · Page 2Linked to original sources
PubMed2026

Canalesolide A, a Structurally Unique Polyhydroxy Macrolide from the Marine Cyanobacterium Okeania sp. with Potent Antitrypanosomal Activity.

The discovery of structurally novel natural products remains central to expanding biologically relevant chemical space, particularly within underexplored marine metabolite classes. Herein, we report the discovery and complete structural elucidation of canalesolide A, a new polyhydroxylated macrolide isolated from the marine cyanobacterium Okeania sp. The compound was identified through an integrated workflow combining phenotypic screening against Trypanosoma brucei and LC-MS/MS-based molecular networking, enabling rapid prioritization of bioactive fractions and dereplication of known metabolite families. Spectroscopic analysis revealed that canalesolide A belongs to the bastimolide-related class of macrolides but exhibits a distinct structural architecture. Its structure was established by integrating ultrahigh-resolution NMR spectroscopy, empirical configurational analysis of polyol systems, targeted model compound synthesis, and controlled chemical degradation and derivatization. This combined strategy resolved stereochemical motifs that were inaccessible by direct analysis of the intact macrolide alone, providing a transferable approach for assigning densely oxygenated marine macrolides. Genome mining identified the putative biosynthetic gene cluster and proposed biosynthetic pathway for a bastimolide-related macrolide. Canalesolide A displays potent, low nanomolar antitrypanosomal activity against human-infective subspecies of T. brucei with rapid elimination of parasites within 1 h at 1 μM. Although moderate mammalian cytotoxicity was observed, preliminary in vivo efficacy/toxicity studies in infected mice suggest a narrow therapeutic window highlighting the need for improved selectivity. This study expands the structural and biosynthetic diversity of polyhydroxylated macrolides and establishes a generalizable framework for resolving stereochemically complex natural products.

Macrolides↗
PubMed2026

Prophage landscapes in clinical MRSA: safety profiling and discovery of Lys81, a broad-spectrum bacteriolytic enzyme.

INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA) poses a significant threat to global healthcare, requiring novel therapeutic strategies. Prophages, latent phage genomes integrated into bacterial chromosomes, are important resources for antimicrobial development due to their genomic stability and genetic engineering potential. METHODS: In this study, we performed genomewide sequencing on 329 MRSA isolates to predict prophage sequences, followed by analyses of these prophages-including examinations of virulence genes, antibiotic resistance genes, homologous proteins of pathogenic MRSA phages, and functional predictions of these homologous proteins-to evaluate their safety and value as genetic engineering scaffolds and to screen for novel broadspectrum bacteriolytic enzymes. RESULTS: Our data indicate that 85.7% (282/329) of strains carried complete prophage sequences; 64 strains lacked virulence factors or genes, meeting the core criteria for safe vectors. Resistance screening found only 6 prophages carried msrA, confirming the biosafety of the remaining strains. A significant correlation existed between prophage virulence gene capacity and genomic structure (R2 = 0.99986684, p = 3.64e-69). High-virulence clusters (>10 factors) showed high structural similarity; 10 characteristic sequences linked to S. aureus phages and their prevalence patterns were identified via conserved motif analysis. Collinearity analysis with reference to virulent MRSA phages and 3D structural predictions of orthologous proteins identified two lysozymes and a host-recognition device. Notably, Lys81, an N-acetylmuramoyl-L-alanine amidase ortholog, was prioritized and characterized as a broad-spectrum lytic enzyme. Our data show Lys81 has key properties: (1) Broad-spectrum antibacterial activity, lysing 52.3% (23/44) of clinical S. aureus strains and cross-acting against Gram-positive bacteria such as Pseudomonas aeruginosa and Listeria; (2) Excellent environmental adaptability, maintaining activity at pH 5.0 and 0°C, with 25 mM Na+ and Ca2 + enhancing function; (3) Potent biofilm clearance, achieving 83% MRSA biofilm reduction at 50 μg/mL; and (4) Favorable in vivo safety/efficacy, eradicating MRSA infections in lung organoid models with minimal cytotoxicity. DISCUSSION: This study establishes a theoretical foundation for the clinical translation of MRSA prophages, positioning Lys81 as a novel candidate for treating drug-resistant bacterial infections.

Lys81↗
PubMed2026

Identification of genomic features that uniquely impact estrogen receptor alpha binding and its effects on gene expression in endometrial cancer.

Estrogen receptor 1 (ESR1, also known as estrogen receptor alpha or ER) is an established oncogenic transcription factor in breast and endometrial cancer; however, more is known about the mechanisms controlling ER behavior in breast cancer, and therapies targeting ER have been much more successful in breast cancer. To address this disparity, we characterize the genomic features that control ER in endometrial cancer and determine to what extent these factors differ from those in breast cancer. We focus on the locations of estrogen response elements (EREs), ER's preferred DNA-binding motif, throughout the human genome. To identify factors that predict ER genomic binding and effects on target gene expression, we apply machine learning to genomic data for each ERE in Ishikawa cells (ER-positive endometrial cancer) and T-47D cells (ER-positive breast cancer). Many of these factors, such as chromatin accessibility and histone modifications, are predictive of ER activity in both cell lines. However, the transcription factors that predict ER activity are cell type specific, including FOXA1 and GATA3 in T-47D cells and ETV4 and SOX17 in Ishikawa cells. In addition, the features that predict ER binding and effects on gene expression differ, with transcription at EREs in the absence of estrogen being predictive of ER regulatory activity. A CRISPR knockout screen in Ishikawa cells, as well as follow-up experiments, confirms the discovery that SOX17 controls ER activity in endometrial cancer cells. These results identify important genomic features of ER binding and regulatory activity and how these features differ between endometrial cancer and breast cancer cells.

Humans↗
PubMed2026

Cytochrome P450- and Dehydrogenase-Mediated Regiospecific and Stereoselective Formation of β- and γ-Lactones in Drimane-Type Sesquiterpenoid Biosynthesis.

Lactone-containing natural products are important candidates for drug discovery. Drimane-type sesquiterpenes (DTSs), characterized by a bicyclic trans-decalin scaffold, can bear both β- and γ-lactone moieties. While γ-lactone-containing DTSs have frequently been reported, β-lactone-containing derivatives are rare, and their biosynthesis remains unexplored. Here, we identified a biosynthetic gene cluster (dri) in Aspergillus ustus and confirmed ustidrimane A (1), a β- and γ-lactone-containing DTS, as its product. Heterologous gene expression, precursor feeding, and enzymatic investigation provided evidence for the formation of both lactone rings. In both cases, the reaction cascade is initiated by regiospecific (and stereoselective) methyl hydroxylation, followed by regiospecific and stereoselective oxidation of one hydroxymethyl group to an aldehyde. The resulting hemiacetal was proven to be subsequently oxidized to a lactone. The β-lactone formation is catalyzed by two cytochrome P450 enzymes (DriE and DriF), followed by two oxidation steps catalyzed by two dehydrogenases (DriG and DriH). These findings differ entirely from the known β-lactone formation in fatty acid-, PKS-, and NRPS-derived metabolites. The subsequent γ-lactone formation is catalyzed by a P450 (DriJ) and a dehydrogenase (DriD). DriJ has been shown to be involved in both methyl hydroxylation and hemiacetal formation, while DriD is responsible for the hemiacetal oxidation and also contributes moderately to its formation. Collectively, these findings establish a sequential P450/dehydrogenase-mediated oxidative cascade for the construction of two distinct lactone motifs within a single DTS scaffold. Moreover, they provide the first insight into the β-lactone formation in terpenes, thus unveiling a new strategy for the construction of this structural motif.

Lactones↗