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PubMed2026

An Acetyltransferase Conferring Self-Resistance of the Producer to Lasso Peptide Antibiotic Lariocidin.

The soil microbiome, a reservoir of antibiotic-producing bacteria, also harbors resistance determinants encoded within antibiotic biosynthetic gene clusters (BGCs). Studying self-resistance mechanisms, which have evolved in producers to protect against their own toxic metabolites, provides critical insights into the evolution of resistance and the potential vulnerabilities of new antibiotics and can facilitate the production of natural products in heterologous hosts. Here, we describe the self-resistance mechanism to lariocidin (LAR), a recently discovered lasso peptide antibiotic that inhibits the ribosomal machinery and exhibits antibacterial activity against key pathogens. We identified and characterized an N-acetyltransferase enzyme (LrcE) encoded within the LAR BGC that mediates self-resistance in LAR-producing Paenibacillus sp. M2. LrcE is a member of the GCN5-related N-acetyltransferase (GNAT) superfamily and performs site-specific acetylation of LAR at a critical lysine residue. This modification disrupts ribosomal binding, thereby reducing LAR's antibacterial activity. Using in silico modeling, we predicted a conserved acetyl-CoA-binding motif and an LAR-binding region on LrcE. Bioinformatic analysis revealed LrcE homologues in environmental but not clinically relevant pathogens, suggesting a limited risk of horizontal gene transfer and, therefore, supporting the further development of LAR as a next-generation antibiotic.

Anti-Bacterial Agents↗

PubMed2026

Accessing Underexplored Biosynthetic Potential by Initiation Unit Engineering of Nonribosomal Peptide Synthetases in Proteobacteria.

Nonribosomal peptide synthetases (NRPSs) represent a valuable yet underexplored resource for producing bioactive natural products. However, most NRPSs remain silenced potentially due to factors such as dysfunction of the initiation unit. The starter condensation (Cs) domain of the initiation unit catalyzes the lipoinitiation of nonribosomal peptides via the incorporation of an N-terminal fatty acyl chain. The concept of initiation unit engineering introduced herein encompasses the replacement of the native initiation unit of NRPSs with a foreign and well-characterized Cs domain-containing initiation unit to activate the NRPS and optimize its expression. This strategy was employed herein to successfully access three of the six previously silent NRPS pathways in Mycetohabitans rhizoxinica HKI 454, a bacterium of the class β-proteobacteria, resulting in the identification of three classes of lipopeptides. This strategy was then extended to access two NRPS pathways in Pseudomonas syringae (γ-proteobacteria) and obtain novel lipopeptides, thereby establishing a feasible complement to existing genome mining strategies for natural product discovery. Furthermore, change of the initiation regions of biosynthetic pathways of nonlipidated chitinimide (β-proteobacteria) and pseudotetraivprolide (γ-proteobacteria) with heterologous Cs-containing initiation units enabled the successful incorporation of fatty acyl chains into the N-terminus of both peptide backbones, launching a workable approach to create artificial lipopeptides. Overall, this study provides a practical strategy for the rational recovery of silent BGCs and introduction of fatty acyl chains into nonribosomal peptides, at least in Proteobacteria, thereby enriching genome mining and combinatorial biosynthesis approaches for accessing the underexplored biosynthetic potential of NRPSs from various bacteria.

Proteobacteria↗

PubMed2025

Exploring biosynthetic potential of the endophytic Penicillium turbatum BLH34 using whole-genome sequence analysis and molecular networking.

An in-depth genomic and metabolomic investigation was conducted on the endophytic fungus Penicillium turbatum BLH34, isolated from Macleaya cordata. Hybrid sequencing (Illumina-Nanopore) generated a high-quality 27.9 Mb genome (GC 48.6%) encoding 9798 proteins, with functional annotation linking 5350 genes to the NCBI non-redundant database and 3404 to KEGG pathways. AntiSMASH analysis uncovered 35 biosynthetic gene clusters (BGCs), 23 of which lacked homology to known pathways, highlighting BLH34's potential for novel metabolite discovery. Molecular networking (GNPS) and LC-MS/MS identified 19 specialised metabolites, including antimicrobial polyketides. Bioassays demonstrated potent inhibition against Staphylococcus aureus (36 mm), Bacillus subtilis (28 mm) and Escherichia coli (24 mm), underscoring its pharmaceutical relevance.

Penicillium↗

PubMed2006

Ovarian cancer and ascites: A questionnaire on current management in the United kingdom.

A questionnaire on ovarian cancer ascites management was sent to members of the British Gynaecological Cancer Society (BGCS), the National Gynaecological Oncology Nurses, and the Assoication of Palliative Medicine. Questions were asked on diuretics, hematologic investigations, paracentesis, and duration of stay. Nine hundred ninety-five questionnaires were distributed, of which 492 replies were received (49% response rate). Fifty-five percent of responders used paracentesis as first-line management of ovarian cancer ascites (15% diuretics). Seventy-five percent performed some blood tests in relation to paracentesis. Ultrasound was used by 43.6% during paracentesis (15.7% for direct visualization, 27.9% to mark an entry site). Seventy-seven percent used a Bonanno catheter. Eighty-three percent used no intravenous fluids during paracentesis, and there was a wide variation in the amount and rate of drainage of ascites (1 L maximum up to free drainage of all ascites, median 5 L; 0.5 L per hour to free drainage). Gynecologists tended to use more interventions (paracentesis, ultrasound, and intravenous fluids) than palliative care physicians or medical oncologists, while palliative care physicians used fewer interventions but admitted patients for longer periods of time. This identified several areas for future study: the value of hematologic investigations, the use of outpatient management for paracentesis, and the use of ultrasound and the rate of drainage of ascites.

Ascites↗

PubMed2025

CAGEcleaner: reducing genomic redundancy in gene cluster mining.

SUMMARY: Mining homologous biosynthetic gene clusters (BGCs) typically involves searching colocalised genes against large genomic databases. However, the high degree of genomic redundancy in these databases often propagates into the resulting hit sets, complicating downstream analyses and visualization. To address this challenge, we present CAGEcleaner, a Python-based pipeline with auxiliary bash scripts designed to reduce redundancy in gene cluster hit sets by dereplicating the genomes that host these hits. CAGEcleaner integrates seamlessly with widely used gene cluster mining tools, such as cblaster and CAGECAT, enabling efficient filtering and streamlining BGC discovery workflows. AVAILABILITY AND IMPLEMENTATION: Source code and documentation is hosted at GitHub (https://github.com/LucoDevro/CAGEcleaner) and Zenodo (https://doi.org/10.5281/zenodo.14726119) under an MIT license. For accessibility, CAGEcleaner is installable from Bioconda (https://anaconda.org/bioconda/cagecleaner) and PyPi (https://pypi.org/project/cagecleaner/), and is also available as a Docker image from DockerHub (https://hub.docker.com/r/lucodevro/cagecleaner).

Software↗

PubMed2026

Oxidative stress induces E. coli aryl polyene expression, sensitizing the bacterial stress response and modulating the redox environment of innate immune cells.

UNLABELLED: Aryl polyenes (APEs) are specialized polyunsaturated outer membrane lipids that protect their producers from oxidative stress and contribute to biofilm formation. APEs are produced by an abundant biosynthetic gene cluster (BGC) family conserved across Gram-negative bacterial clades. The APE biosynthesis pathway involves 11 different enzymes and culminates in the attachment of APEs to an anchor molecule in the Gram-negative outer membrane. Unlike most other small molecule BGCs, the APE BGC does not contain a dedicated regulatory gene that controls the production of its metabolically costly compounds. Building from our prior observations of APEs' role in acute oxidative stress protection, we use a uropathogenic Escherichia coli (UPEC) strain to show that APE expression conveys a potential competitive advantage characterized by increased early-stage growth, sensitization of the bacterial oxidative stress response, and dampening of the redox stress of innate immune cells after in vitro infection. Our data indicate that APEs could act as a UPEC fitness factor, and in future work, we aim to study their contribution to overall bacterial pathogenicity and survival, as well as how APEs could facilitate the transition from an oxygen-poor environment, such as the gut, to the oxygen-rich environment of the urinary tract. IMPORTANCE: Bacterial pathogens use various mechanisms to achieve a competitive advantage under harsh conditions, such as during interactions with their host. We studied the function of aryl polyenes (APEs), specialized polyunsaturated fatty acids in the outer membrane, in the context of a uropathogenic E. coli strain. APE expression is induced by an oxidative environment and contributes to early-stage growth and sensitization of the oxidative stress response. Furthermore, APE-expressing E. coli dampen the intracellular oxidative milieu of target host phagocytes. These findings suggest a role for APEs as a fitness factor and create opportunities to study their in vivo function and explore them as a potential drug target.

Oxidative Stress↗

PubMedDate not supplied

Cognitive and psychomotor function during hypoglycemia: a comparison between porcine and human insulin.

After an overnight euglycemic clamp, blood glucose levels were precisely lowered on two nonconsecutive mornings via a glucose-controlled insulin infusion system (GCIIS, Biostator) using either purified porcine insulin (PPI) or human insulin (HI). Two cognitive and psychomotor tests were significantly different in 8 type-I diabetic subjects and 8 healthy volunteers at four timepoints, when mean blood glucose concentrations (BGCs) were 100, 65, 50, and 40 mg/dl. Also, a significant difference (p = 0.005) could be found between the mean of all reaction time testing (RTT) values under HI as compared with the mean of all RTT values under PPI. Lowering the BGC resulted in a significant increase in the reaction time (p = 0.012). These effects were not dependent on the type of insulin being used nor were they typical of a particular study group.

Adolescent↗

PubMed2025

Multi-Omics and Integrative Analytics in Natural Products Discovery.

Natural products (NPs) have long been an essential source of new bioactive compounds for drug discovery; however, traditional methods for screening and isolating these compounds can be slow and often yield diminishing returns. Fortunately, advanced multi-omics and computational approaches present powerful solutions to these challenges. This review highlights innovative methodologies that integrate metabolomics, genomics, transcriptomics, and proteomics with bioinformatics and analytical chemistry to accelerate NP discovery. For instance, untargeted metabolomics platforms like high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS) and Global Natural Products Social (GNPS) molecular networking allow for comprehensive profiling of new compounds, while targeted isotope-labeling strategies enhance this process. Additionally, genome and metagenome mining tools such as antibiotics and secondary metabolite analysis shell (antiSMASH), Deep Biosynthetic Gene Cluster (DeepBGC), and Pipeline for Reconstructing Integrated Syntheses of Metabolites (PRISM) quickly identify biosynthetic gene clusters (BGCs) in both cultured and uncultured organisms, often using heterologous expression to validate products. Transcriptomic analyses, including RNA sequencing (RNA-seq), co-expression networks, and fluxomics, help clarify how pathways are regulated, while quantitative proteomics techniques like tandem mass tags/isobaric tags for relative and absolute quantitation (TMT/iTRAQ) and label-free methods, along with chemoproteomics approaches such as cellular thermal shift assay and thermal proteome profiling (TPP), uncover molecular targets and their mechanisms of action. This review also places significant emphasis on the role of artificial intelligence (AI) and machine learning (ML) in integrating multi-omics data, spanning activities from constructing gene-metabolite correlation networks to leveraging knowledge graphs and graph neural networks for data fusion and functional prediction. Finally, this review concludes by discussing the synergistic benefits of multi-omics for natural-product discovery, addressing current technical challenges, and exploring future directions toward high-throughput, intelligent data integration for next-generation NP research.

Biological Products↗

PubMed2026

Cross-Kingdom Siderophores: Biosynthesis, Ecology, and Biotechnological Applications.

Microbial siderophores are high-affinity iron-binding compounds which are produced by bacteria, fungi, and actinomycetes to obtain iron and survive and interact with different species in an iron-deficient environment. While the conventional research on siderophore systems deals mainly with the study within the same taxa, modern researchers have increased their inclination toward cross-kingdom integration of siderophore behavior and their impact on host-associated environments. This can be largely attributed to differences in biosynthetic gene clusters, receptor systems, and regulatory networks, which produce distinct genotype-to-phenotype results determining microbial cooperation and competition. Current advancements in genomic research, together with omics studies like transcriptomics, proteomics, and metabolomics, have created newer insights into how siderophores function. However, the present literature evidences multiple major gaps in multi-omics data because the link between genomes and metabolomes remains weak due to inconsistent regulatory data sets and failure in identifying producer-consumer relationships in polymicrobial systems. Additionally, major constraints like molecular instability, delivery system limitations, host toxicity, limitations in upscaling, and regulatory issues delimit the use of siderophores in medical treatment, agricultural practices, and environmental biotechnology. This review aims to bridge the existing knowledge about siderophore biochemistry, biosynthesis, ecological functions, and genetic regulation across kingdoms while integrating multi-omics outlook with translational considerations. Thus, by connecting molecular mechanisms with evolutionary cross-talk, this study aims to provide a system-level framework in the world of siderophore-mediated iron uptake and therefore shapes future directions in emerging fields of microbial engineering, precision therapies, and sustainable biotechnology.

Fur regulation↗

PubMed2026

Genomic signatures of host-range divergence in the generalist Beauveria bassiana and the specialist Beauveria brongniartii.

Entomopathogenic fungi of the genus Beauveria are widely used biological control agents that infect diverse insect hosts and can also associate with plants as rhizosphere colonizers and endophytes. Within this genus, Beauveria bassiana is a cosmopolitan generalist, whereas Beauveria brongniartii exhibits a narrower host range, primarily targeting soil-dwelling coleopteran larvae with limited evidence of plant colonization. To explore genomic differentiation associated with this ecological divergence, the commercially exploited B. brongniartii strain BIPESCO2 and B. bassiana ATHUM 4946 were sequenced using Oxford Nanopore technology, followed by comparative genomic analyses across multiple strains. Orthology identified species-specific gene families, although overall genome architecture and core gene content were highly conserved. The CAZyme repertoires were nearly identical, indicating retention of a versatile enzymatic toolkit supporting plant association, saprotrophy, and insect pathogenicity. In contrast, biosynthetic gene clusters displayed substantial variation, including structural remodeling of Beauveria-specific virulence-associated clusters and expansion of type I polyketide synthase clusters in B. brongniartii. Effector prediction revealed a conserved core of largely uncharacterized proteins alongside species-specific orthogroups enriched in adhesion-, immunity-, and cuticle-interaction domains. Together, these findings indicate that host-range divergence in Beauveria is associated with compartmentalized genomic differentiation, particularly in secondary metabolism and a limited subset of lineage-specific virulence factors, rather than in the conserved core infection machinery.

Beauveria↗