Dereplication of Natural Product Antifungals via Liquid Chromatography-Tandem Mass Spectrometry and Chemical Genomics.

Recently expanded reports of multidrug-resistant fungal infections underscore the need to develop new and more efficient methods for antifungal drug discovery. A ubiquitous problem in natural product drug discovery campaigns is the rediscovery of known compounds or their relatives; accordingly, we have integrated Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) for structural dereplication and Yeast Chemical Genomics for bioprocess evaluation into a screening platform to identify such compounds early in the screening process. We identified 450 fractions inhibiting and the resistant strains of and among more than 40,000 natural product fractions.

Expert consensus on the benefits of neuraminidase in conventional influenza vaccines: a Delphi study.

Background: Seasonal vaccination is the mainstay of human influenza prevention. Licensed influenza vaccines are regularly updated to account for viral mutations and antigenic drift and are standardised for their haemagglutinin content. However, vaccine effectiveness remains suboptimal.

The Janus Effect: The Biochemical Logic of Antibiotic Resistance.

Antibiotics are essential medicines threatened by the emergence of resistance in all relevant bacterial pathogens. The engagement of the molecular targets of antibiotics offers multiple opportunities for resistance to emerge. Successful target engagement often requires passage of the antibiotic from outside into the cell interior through one or two distinct membrane barriers.

Revisiting the potential of natural products in antimycobacterial therapy: advances in drug discovery and semisynthetic solutions.

Natural products have been pivotal in treating mycobacterial infections with early antibiotics such as streptomycin, forming the foundation of tuberculosis therapy. However, the emergence of multidrug-resistant and extensively drug-resistant Mycobacterium species has intensified the need for novel antimycobacterial agents. In this review, we revisit the historical contributions of natural products to antimycobacterial drug discovery and highlight recent advances in the field.

SARS-CoV-2 Illumina GeNome Assembly Line (SIGNAL), a Snakemate workflow for rapid and bulk analysis of Illumina sequencing of SARS-CoV-2 genomes.

The incorporation of sequencing technologies in frontline and public health healthcare settings was vital in developing virus surveillance programs during the Coronavirus Disease 2019 (COVID-19) pandemic caused by transmission of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, increased data acquisition poses challenges for both rapid and accurate analyses. To overcome these hurdles, we developed the SARS-CoV-2 Illumina GeNome Assembly Line (SIGNAL) for quick bulk analyses of Illumina short-read sequencing data.

Examining the molecular clock hypothesis for the contemporary evolution of the rabies virus.

The molecular clock hypothesis assumes that mutations accumulate on an organism's genome at a constant rate over time, but this assumption does not always hold true. While modelling approaches exist to accommodate deviations from a strict molecular clock, assumptions about rate variation may not fully represent the underlying evolutionary processes. There is considerable variability in rabies virus (RABV) incubation periods, ranging from days to over a year, during which viral replication may be reduced.

Early-life upper airway microbiota are associated with decreased lower respiratory tract infections.

Background: Microbial interactions mediating colonization resistance play key roles within the human microbiome, shaping susceptibility to infection from birth. The role of the nasal and oral microbiome in the context of early life respiratory infections and subsequent allergic disease risk remains understudied.

Objectives: Our aim was to gain insight into microbiome-mediated defenses and respiratory pathogen colonization dynamics within the upper respiratory tract during infancy.

Farm exposure is associated with human breast milk immune profile and microbiome.

Prenatal and early life farm exposure, and breastfeeding, are associated with protection from allergic diseases. We hypothesize that farm exposure influences the human breast milk microbiome and immune proteins. The immune protein profiles and microbial communities of 152 human breast milk samples were compared among three maternal farm exposure groups (traditional agrarian, farm, and non-farm) in rural Wisconsin to identify signatures associated with farm status and atopic disease.

Upper respiratory microbial communities of healthy populations are shaped by niche and age.

Background: Alterations in upper respiratory microbiomes have been implicated in shaping host health trajectories, including by limiting mucosal pathogen colonization. However, limited comparative studies of respiratory microbiome development and functioning across age groups have been performed. Herein, we perform shotgun metagenomic sequencing paired with pathogen inhibition assays to elucidate differences in nasal and oral microbiome composition and intermicrobial interactions across healthy 24-month-old infant (n = 229) and adult (n = 100) populations.

LPS-induced lung tissue-resident trained innate immunity provides differential protection against pneumococci and SARS-CoV-2.

Recent evidence indicates that tissue-resident innate immune memory and trained innate immunity (TII) can be induced centrally in myeloid cells within the bone marrow and locally in tissue-resident macrophages in respiratory mucosal tissues. However, it remains unclear whether acute exposure to airborne microbial components like lipopolysaccharide (LPS) induces lasting innate immune memory in airway macrophages and TII capable of protection against heterologous pathogens. Using a murine model, we demonstrate that acute LPS exposure leads to dynamic changes in the immune phenotype of airway macrophages that persist long after the acute inflammatory response has subsided.

Efficacy of aspergillomarasmine A/meropenem combinations with and without avibactam against bacterial strains producing multiple β-lactamases.

The effectiveness of β-lactam antibiotics is increasingly threatened by resistant bacteria that harbor hydrolytic β-lactamase enzymes. Depending on the class of β-lactamase present, β-lactam hydrolysis can occur through one of two general molecular mechanisms. Metallo-β-lactamases (MBLs) require active site Zn ions, whereas serine-β-lactamases (SBLs) deploy a catalytic serine residue.

Canada's provincial COVID-19 pandemic modelling efforts: A review of mathematical models and their impacts on the responses.

Setting: Mathematical modelling played an important role in the public health response to COVID-19 in Canada. Variability in epidemic trajectories, modelling approaches, and data infrastructure across provinces provides a unique opportunity to understand the factors that shaped modelling strategies.

Intervention: Provinces implemented stringent pandemic interventions to mitigate SARS-CoV-2 transmission, considering evidence from epidemic models.

The porcine skin microbiome exhibits broad fungal antagonism.

The skin and its microbiome function to protect the host from pathogen colonization and environmental stressors. In this study, using the Wisconsin Miniature Swine™ model, we characterize the porcine skin fungal and bacterial microbiomes, identify bacterial isolates displaying antifungal activity, and use whole-genome sequencing to identify biosynthetic gene clusters encoding for secondary metabolites that may be responsible for the antagonistic effects on fungi. Through this comprehensive approach of paired microbiome sequencing with culturomics, we report the discovery of novel species of Corynebacterium and Rothia.

Key aspects of papillomavirus infection influence the host cervicovaginal microbiome in a preclinical murine papillomavirus (MmuPV1) infection model.

Human papillomaviruses (HPVs) are the most common sexually transmitted infection in the United States and are a major etiological agent of cancers in the anogenital tract and oral cavity. Growing evidence suggests changes in the host microbiome are associated with the natural history and ultimate outcome of HPV infection. We sought to define changes in the host cervicovaginal microbiome during papillomavirus infection, persistence, and pathogenesis using the murine papillomavirus (MmuPV1) cervicovaginal infection model.

Targeting bacterial nickel transport with aspergillomarasmine A suppresses virulence-associated Ni-dependent enzymes.

Microbial Ni homeostasis underpins the virulence of several clinical pathogens. Ni is an essential cofactor in urease and [NiFe]-hydrogenases involved in colonization and persistence. Many microbes produce metallophores to sequester metals necessary for their metabolism and starve competing neighboring organisms.

Upper respiratory microbial communities of healthy populations are shaped by niche and age.

Background: Alterations in upper respiratory microbiomes have been implicated in shaping host health trajectories, including by limiting mucosal pathogen colonization. However, limited comparative studies of respiratory microbiome development and functioning across age groups have been performed. Herein, we perform shotgun metagenomic sequencing paired with pathogen inhibition assays to elucidate differences in nasal and oral microbiome composition and functioning across healthy 24-month-old infant (n=229) and adult (n=100) populations.

Chronic TNF exposure induces glucocorticoid-like immunosuppression in the alveolar macrophages of aged mice that enhances their susceptibility to pneumonia.

Chronic low-grade inflammation, particularly elevated tumor necrosis factor (TNF) levels, occurs due to advanced age and is associated with greater susceptibility to infection. One reason for this is age-dependent macrophage dysfunction (ADMD). Herein, we use the adoptive transfer of alveolar macrophages (AM) from aged mice into the airway of young mice to show that inherent age-related defects in AM were sufficient to increase the susceptibility to Streptococcus pneumoniae, a Gram-positive bacterium and the leading cause of community-acquired pneumonia.

Allosteric inhibition of tRNA synthetase Gln4 by N-pyrimidinyl-β-thiophenylacrylamides exerts highly selective antifungal activity.

Candida species are among the most prevalent causes of systemic fungal infections, which account for ∼1.5 million annual fatalities. Here, we build on a compound screen that identified the molecule N-pyrimidinyl-β-thiophenylacrylamide (NP-BTA), which strongly inhibits Candida albicans growth.

Disturbance-diversity relationships of microbial communities change based on growth substrate.

Disturbance events can impact ecological community dynamics. Understanding how communities respond to disturbances and how those responses can vary is a challenge in microbial ecology. In this study, we grew a previously enriched specialized microbial community on either cellulose or glucose as a sole carbon source and subjected them to one of five different disturbance regimes of varying frequencies ranging from low to high.

Lessons from assembling a microbial natural product and pre-fractionated extract library in an academic laboratory.

Unlabelled: Microbial natural products are specialized metabolites that are sources of many bioactive compounds including antibiotics, antifungals, antiparasitics, anticancer agents, and probes of biology. The assembly of libraries of producers of natural products has traditionally been the province of the pharmaceutical industry. This sector has gathered significant historical collections of bacteria and fungi to identify new drug leads with outstanding outcomes-upwards of 60% of drug scaffolds originate from such libraries.