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.

Cytomegalovirus-Specific T-Cell-Receptor-like Antibodies Target In Vivo-Infected Human Leukocytes Inducing Natural Killer Cell-Mediated Antibody-Dependent Cellular Cytotoxicity.

Cytomegalovirus (CMV) reactivation after stem cell or solid organ transplantation remains a major cause of morbidity and mortality in this setting. T-cell receptor (TCR)-like antibodies bind to intracellular peptides presented in major histocompatibility complex (MHC) molecules on the cell surface and may have the potential to replace T-cell function in immunocompromised patients. Three previously selected CMV-specific, human leukocyte antigen (HLA)-restricted (HLA-A*0101, HLA-A*0201 and HLA-B*0702) Fab-antibodies (A6, C1 and C7) were produced as IgG antibodies with Fc optimization.

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 unpreceded 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.

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.

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).

Thermo-amplifier circuit in probiotic E. coli for stringently temperature-controlled release of a novel antibiotic.

Peptide drugs have seen rapid advancement in biopharmaceutical development, with over 80 candidates approved globally. Despite their therapeutic potential, the clinical translation of peptide drugs is hampered by challenges in production yields and stability. Engineered bacterial therapeutics is a unique approach being explored to overcome these issues by using bacteria to produce and deliver therapeutic compounds at the body site of use.

Targeting the IspE Enzyme.

The enzyme IspE in is considered an attractive drug target, as it is essential for parasite survival and is absent in the human proteome. Yet it still has not been addressed by a small-molecule inhibitor. In this study, we conducted a high-throughput screening campaign against the IspE enzyme.

Total Synthesis and Configuration Assignment of (+)-Myxoquaterine-450.

Myxoquaterines represent a recently discovered class of natural products with intriguing biological properties. They were isolated from Pendulasporacea albinea MSr 11954 and display a unique structure combining heterocyclic (pyrrole, oxazoline), hexaene, and 2-amino-1,3-diol subunits. We have now synthesized the first example of a myxoquaterine natural product, myxoquaterine-450, in a highly convergent fashion, in which the sensitive hexaene unit was established in the final stages of the synthesis (16 linear steps starting from l-serine).

IspE kinase as an anti-infective target: Role of a hydrophobic pocket in inhibitor binding.

Enzymes of the methylerythritol phosphate (MEP) pathway are potential targets for antimicrobial drug discovery. Here, we focus on 4-diphosphocytidyl-2-C-methyl-D-erythritol (IspE) kinase from the MEP pathway. We use biochemical and structural biology methods to investigate homologs from pathogenic microorganisms; Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii.

Synthesis and antibiotic potential of myxocoumarin-inspired chromene dione analogs.

The rapid emergence of antibiotic resistance in recent years poses a substantial global health threat. Thus, the discovery of potent novel antibiotics is of utmost importance. One such compound class with promising antibiotic potential are the myxocoumarins from MYX-030, which exhibit exceptional antibiotic activities against several Gram-positive pathogens, including MRSA.

Harnessing Gram-negative bacteria for novel anti-Gram-negative antibiotics.

Natural products have proven themselves as a valuable resource for antibiotics. However, in view of increasing antimicrobial resistance, there is an urgent need for new, structurally diverse agents that have the potential to overcome resistance and treat Gram-negative pathogens in particular. Historically, the search for new antibiotics was strongly focussed on the very successful Actinobacteria.

Expression and characterization of pantothenate energy-coupling factor transporters as an anti-infective drug target.

This study investigates the potential of energy-coupling factor (ECF) transporters as promising anti-infective targets to combat antimicrobial resistance (AMR). ECF transporters, a subclass of ATP-binding cassette (ABC) transporters, facilitate the uptake of B-vitamins across bacterial membranes by utilizing ATP as an energy source. Vitamins are essential cofactors for bacterial metabolism and growth, and they can either be synthesized de novo or absorbed from the environment.

BGC Atlas: a web resource for exploring the global chemical diversity encoded in bacterial genomes.

Secondary metabolites are compounds not essential for an organism's development, but provide significant ecological and physiological benefits. These compounds have applications in medicine, biotechnology and agriculture. Their production is encoded in biosynthetic gene clusters (BGCs), groups of genes collectively directing their biosynthesis.