Expanding the immune-related targetome of miR-155-5p by integrating time-resolved RNA patterns into miRNA target prediction.

The lack of a sufficient number of validated miRNA targets severely hampers the understanding of their biological function. Even for the well-studied miR-155-5p, there are only 239 experimentally validated targets out of 42,554 predicted targets. For a more complete assessment of the immune-related miR-155 targetome, we used an inverse correlation of time-resolved mRNA profiles and miR-155-5p expression of early CD4+ T cell activation to predict immune-related target genes.

Targeting IspD for Anti-infective and Herbicide Development: Exploring Its Role, Mechanism, and Structural Insights.

Antimicrobial resistance (AMR) and herbicide resistance pose threats to society, necessitating novel anti-infectives and herbicides exploiting untapped modes of action like inhibition of IspD, the third enzyme in the MEP pathway. The MEP pathway is essential for a wide variety of human pathogens, including , , and as well as plants. Within the current perspective, we focused our attention on the third enzyme in this pathway, IspD, offering a comprehensive summary of the reported modes of inhibition and common trends, with the goal to inspire future research dedicated to this underexplored target.

A fucose-binding superlectin from Enterobacter cloacae with high Lewis and ABO blood group antigen specificity.

Bacteria frequently employ carbohydrate-binding proteins, so-called lectins, to colonize and persist in a host. Thus, bacterial lectins are attractive targets for the development of new antiinfectives. To find new potential targets for antiinfectives against pathogenic bacteria, we searched for homologs of Pseudomonas aeruginosa lectins and identified homologs of LecA in Enterobacter species.

Chemoenzymatic C,C-Bond Forming Cascades by Cryptic Vanadium Haloperoxidase Catalyzed Bromination.

Inspired by natural cryptic halogenation in -bond formation, this study developed a synthetic approach combining biocatalytic bromination with transition-metal-catalyzed cross-coupling. Using the cyanobacterial VHPO, a robust and sustainable bromination-arylation cascade was created. Genetic modifications allowed enzyme immobilization, enhancing the compatibility between biocatalysis and chemocatalysis.

High-Affinity Lectin Ligands Enable the Detection of Pathogenic Biofilms: Implications for Diagnostics and Therapy.

is a critical priority pathogen and causes life-threatening acute and biofilm-associated chronic infections. The choice of suitable treatment for complicated infections requires lengthy culturing for species identification from swabs or an invasive biopsy. To date, no fast, pathogen-specific diagnostic tools for infections are available.

Systematic assessment of COVID-19 host genetics using whole genome sequencing data.

Courses of SARS-CoV-2 infections are highly variable, ranging from asymptomatic to lethal COVID-19. Though research has shown that host genetic factors contribute to this variability, cohort-based joint analyses of variants from the entire allelic spectrum in individuals with confirmed SARS-CoV-2 infections are still lacking. Here, we present the results of whole genome sequencing in 1,220 mainly vaccine-naïve individuals with confirmed SARS-CoV-2 infection, including 827 hospitalized COVID-19 cases.

GOLD COPD Exacerbation History Categories and Disease Outcomes.

Importance: Previous exacerbations of chronic obstructive pulmonary disease (ECOPD) are associated with future events. For more than a decade, patients at high risk have been defined as individuals with a history of 2 or more moderate ECOPD, 1 or more severe ECOPD, or both within 12 months, and treatments have been allocated accordingly, but these cutoffs lack validation.

Objectives: To validate ECOPD history categories by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) and explore alternative cutoffs to estimate moderate and severe ECOPD and all-cause mortality in COPD.

Fragment Discovery by X-Ray Crystallographic Screening Targeting the CTP Binding Site of Pseudomonas Aeruginosa IspD.

With antimicrobial resistance (AMR) reaching alarming levels, new anti-infectives with unprecedented mechanisms of action are urgently needed. The 2-C-methylerythritol-D-erythritol-4-phosphate (MEP) pathway represents an attractive source of drug targets due to its essential role in numerous pathogenic Gram-negative bacteria and Mycobacterium tuberculosis (Mt), whilst being absent in human cells. Here, we solved the first crystal structure of Pseudomonas aeruginosa (Pa) IspD, the third enzyme in the MEP pathway and present the discovery of a fragment-based compound class identified through crystallographic screening of PaIspD.

Autologous DNA mobilization and multiplication expedite natural products discovery from bacteria.

The transmission of antibiotic-resistance genes, comprising mobilization and relocation events, orchestrates the dissemination of antimicrobial resistance. Inspired by this evolutionarily successful paradigm, we developed ACTIMOT, a CRISPR-Cas9-based approach to unlock the vast chemical diversity concealed within bacterial genomes. ACTIMOT enables the efficient mobilization and relocation of large DNA fragments from the chromosome to replicative plasmids within the same bacterial cell.

MIBiG 4.0: advancing biosynthetic gene cluster curation through global collaboration.

Specialized or secondary metabolites are small molecules of biological origin, often showing potent biological activities with applications in agriculture, engineering and medicine. Usually, the biosynthesis of these natural products is governed by sets of co-regulated and physically clustered genes known as biosynthetic gene clusters (BGCs). To share information about BGCs in a standardized and machine-readable way, the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard and repository was initiated in 2015.

Association of Patients' Knowledge on the Disease and Its Management with Indicators of Disease Severity and Individual Characteristics in Patients with Chronic Obstructive Pulmonary Disease (COPD): Results from COSYCONET 2.

Background: In patients with chronic diseases, including those with chronic obstructive pulmonary disease (COPD), knowledge on the disease and its self-management is considered as relevant for improving disease control and long-term outcome. We studied to which extent components of knowledge depended on potential predictors, such as participation in educational programs and disease severity. For example, the perception of exacerbations or GOLD grade might modulate the content and reliability of COPD understanding.

Exquisite selectivity of griselimycin extends to beta subunit of DNA polymerases from Gram-negative bacterial pathogens.

Griselimycin, a cyclic depsidecapeptide produced by Streptomyces griseus, is a promising lead inhibitor of the sliding clamp component of bacterial DNA polymerases (β-subunit of Escherichia coli DNA pol III). It was previously shown to inhibit the Mycobacterium tuberculosis β-clamp with remarkably high affinity and selectivity - the peptide lacks any interaction with the human sliding clamp. Here, we used a structural genomics approach to address the prospect of broader-spectrum inhibition, in particular of β-clamps from Gram-negative bacterial targets.

Integral Solvent-Induced Protein Precipitation for Target-Engagement Studies in .

The limited understanding of the mechanism of action (MoA) of several antimalarials and the rise of drug resistance toward existing malaria therapies emphasizes the need for new strategies to uncover the molecular target of compounds in . Integral solvent-induced protein precipitation (iSPP) is a quantitative mass spectrometry-based (LC-MS/MS) proteomics technique. The iSPP leverages the change in solvent-induced denaturation of the drug-bound protein relative to its unbound state, allowing identification of the direct drug-protein target without the need to modify the drug.

Mechanisms of tigecycline resistance in Gram-negative bacteria: A narrative review.

Tigecycline serves as a critical "final-resort" antibiotic for treating bacterial infections caused by multidrug-resistant bacteria for which treatment options are severely limited. The increasing prevalence of tigecycline resistance, particularly among Gram-negative bacteria, is a major concern. Various mechanisms have been identified as contributors to tigecycline resistance, including upregulation of nonspecific Resistance Nodulation Division (RND) efflux pumps due to mutations in transcriptional regulators, enzymatic modification of tigecycline by monooxygenase enzymes, and mutations affecting tigecycline binding sites.

Homophenylalanine-derived benzo[1,4]diazepine-2,5-diones are strong bacterial quorum sensing inhibitors.

Benzo[1,4]diazepines show a large diversity of biological activities and are still commonly used as medications against a broad range of diseases. Within our research in the field of chemo-enzymatic alkaloid synthesis, we developed a synthetic route towards close structural relatives, namely benzo[1,4]diazepine-2,5-diones. Possible antimicrobial activities of these substances are barely known up to date.

Olikomycin A-A Novel Calcium-Dependent Lipopeptide with Antibiotic Activity Against Multidrug-Resistant Bacteria.

Research into new antibiotics is becoming increasingly important as antibiotic resistance increases worldwide. The genus Streptomyces in particular is able to produce a wide range of antimicrobial products due to the large number of biosynthetic gene clusters (BGCs) in its genome. However, not all BGCs are expressed under laboratory conditions.

Studying Target-Engagement of Anti-Infectives by Solvent-Induced Protein Precipitation and Quantitative Mass Spectrometry.

Antimicrobial resistance (AMR) poses a serious threat to global health. The rapid emergence of resistance contrasts with the slow pace of antimicrobial development, emphasizing the urgent need for innovative drug discovery approaches. This study addresses a critical bottleneck in early drug development by introducing integral solvent-induced protein precipitation (iSPP) to rapidly assess the target-engagement of lead compounds in extracts of pathogenic microorganisms under close-to-physiological conditions.

The PLSDB 2025 update: enhanced annotations and improved functionality for comprehensive plasmid research.

Plasmids are extrachromosomal DNA molecules in bacteria and archaea, playing critical roles in horizontal gene transfer, antibiotic resistance, and pathogenicity. Since its first release in 2018, our database on plasmids, PLSDB, has significantly grown and enhanced its content and scope. From 34 513 records contained in the 2021 version, PLSDB now hosts 72 360 entries.

In Vivo Activity Profiling of Biosynthetic Darobactin D22 against Critical Gram-Negative Pathogens.

In recent years, naturally occurring darobactins have emerged as a promising compound class to combat infections caused by critical Gram-negative pathogens. In this study, we describe the in vivo evaluation of derivative D22, a non-natural biosynthetic darobactin analogue with significantly improved antibacterial activity. We found D22 to be active in vivo against key critical Gram-negative human pathogens, as demonstrated in murine models of thigh infection, peritonitis/sepsis, and urinary tract infection (UTI).