Parenteral BCG vaccine induces lung-resident memory macrophages and trained immunity via the gut-lung axis.

Aside from centrally induced trained immunity in the bone marrow (BM) and peripheral blood by parenteral vaccination or infection, evidence indicates that mucosal-resident innate immune memory can develop via a local inflammatory pathway following mucosal exposure. However, whether mucosal-resident innate memory results from integrating distally generated immunological signals following parenteral vaccination/infection is unclear. Here we show that subcutaneous Bacillus Calmette-Guérin (BCG) vaccination can induce memory alveolar macrophages (AMs) and trained immunity in the lung.

The future of fungi: threats and opportunities.

The fungal kingdom represents an extraordinary diversity of organisms with profound impacts across animal, plant, and ecosystem health. Fungi simultaneously support life, by forming beneficial symbioses with plants and producing life-saving medicines, and bring death, by causing devastating diseases in humans, plants, and animals. With climate change, increased antimicrobial resistance, global trade, environmental degradation, and novel viruses altering the impact of fungi on health and disease, developing new approaches is now more crucial than ever to combat the threats posed by fungi and to harness their extraordinary potential for applications in human health, food supply, and environmental remediation.

Protocol for isolation and characterization of lung tissue resident memory T cells and airway trained innate immunity after intranasal vaccination in mice.

Vaccination route dictates the quality and localization of immune responses within tissues. Intranasal vaccination seeds tissue-resident adaptive immunity, alongside trained innate responses within the lung/airways, critical for superior protection against SARS-CoV-2. This protocol encompasses intranasal vaccination in mice, step-by-step bronchoalveolar lavage for both cellular and acellular airway components, lung mononuclear cell isolation, and detailed flow cytometric characterization of lung tissue-resident memory T cell responses, and airway macrophage-trained innate immunity.

The past, present, and future of antibiotics.

Antibiotics have transformed modern medicine. They are essential for treating infectious diseases and enable vital therapies and procedures. However, despite this success, their continued use in the 21st century is imperiled by two orthogonal challenges.

The unmitigated profile of COVID-19 infectiousness.

Quantifying the temporal dynamics of infectiousness of individuals infected with SARS-CoV-2 is crucial for understanding the spread of COVID-19 and for evaluating the effectiveness of mitigation strategies. Many studies have estimated the infectiousness profile using observed serial intervals. However, statistical and epidemiological biases could lead to underestimation of the duration of infectiousness.

HelR is a helicase-like protein that protects RNA polymerase from rifamycin antibiotics.

Rifamycin antibiotics such as rifampin are potent inhibitors of prokaryotic RNA polymerase (RNAP) used to treat tuberculosis and other bacterial infections. Although resistance arises in the clinic principally through mutations in RNAP, many bacteria possess highly specific enzyme-mediated resistance mechanisms that modify and inactivate rifamycins. The expression of these enzymes is controlled by a 19-bp cis-acting rifamycin-associated element (RAE).

Differential Biodistribution of Adenoviral-Vectored Vaccine Following Intranasal and Endotracheal Deliveries Leads to Different Immune Outcomes.

Infectious diseases of the respiratory tract are one of the top causes of global morbidity and mortality with lower respiratory tract infections being the fourth leading cause of death. The respiratory mucosal (RM) route of vaccine delivery represents a promising strategy against respiratory infections. Although both intranasal and inhaled aerosol methods have been established for human application, there is a considerable knowledge gap in the relationship of vaccine biodistribution to immune efficacy in the lung.

Targeting fungal membrane homeostasis with imidazopyrazoindoles impairs azole resistance and biofilm formation.

Fungal infections cause more than 1.5 million deaths annually. With an increase in immune-deficient susceptible populations and the emergence of antifungal drug resistance, there is an urgent need for novel strategies to combat these life-threatening infections.

The importance of the generation interval in investigating dynamics and control of new SARS-CoV-2 variants.

Inferring the relative strength (i.e. the ratio of reproduction numbers) and relative speed (i.

Machine Learning for Antimicrobial Resistance Prediction: Current Practice, Limitations, and Clinical Perspective.

Antimicrobial resistance (AMR) is a global health crisis that poses a great threat to modern medicine. Effective prevention strategies are urgently required to slow the emergence and further dissemination of AMR. Given the availability of data sets encompassing hundreds or thousands of pathogen genomes, machine learning (ML) is increasingly being used to predict resistance to different antibiotics in pathogens based on gene content and genome composition.

Inhibiting C-4 Methyl Sterol Oxidase with Novel Diazaborines to Target Fungal Plant Pathogens.

With resistance to current agricultural fungicides rising, a great need has emerged for new antifungals with unexploited targets. In response, we report a novel series of diazaborines with potent activity against representative fungal plant pathogens. To identify their mode of action, we selected for resistant isolates using the model fungus .

The need for linked genomic surveillance of SARS-CoV-2.

Genomic surveillance during the coronavirus disease 2019 (COVID-19) pandemic has been key to the timely identification of virus variants with important public health consequences, such as variants that can transmit among and cause severe disease in both vaccinated or recovered individuals. The rapid emergence of the Omicron variant highlighted the speed with which the extent of a threat must be assessed. Rapid sequencing and public health institutions' openness to sharing sequence data internationally give an unprecedented opportunity to do this; however, assessing the epidemiological and clinical properties of any new variant remains challenging.

Glycopeptide antibiotic discovery in the genomic era.

Glycopeptide antibiotics are essential drugs used to treat infections caused by multi-drug resistant Gram-positive pathogens. There is a continuous need for new antibiotics, including GPAs, to address emerging resistance and offer desirable pharmacological profiles for improved efficacy. Microbial natural products are proven sources of antibiotics, and this source has dominated drug discovery over the past century.

Structural and molecular rationale for the diversification of resistance mediated by the Antibiotic_NAT family.

The environmental microbiome harbors a vast repertoire of antibiotic resistance genes (ARGs) which can serve as evolutionary predecessors for ARGs found in pathogenic bacteria, or can be directly mobilized to pathogens in the presence of selection pressures. Thus, ARGs from benign environmental bacteria are an important resource for understanding clinically relevant resistance. Here, we conduct a comprehensive functional analysis of the Antibiotic_NAT family of aminoglycoside acetyltransferases.

Prevalence and characteristics of progressive fibrosing interstitial lung disease in a prospective registry.

Background: Progressive fibrosing interstitial lung disease (PF-ILD) is characterised by progressive physiological, symptomatic and/or radiographic worsening. The real-world prevalence and characteristics of PF-ILD remain uncertain.

Methods: Patients were enrolled from the Canadian Registry for Pulmonary Fibrosis between 2015 and 2020.

Exploratory Growth in Streptomyces venezuelae Involves a Unique Transcriptional Program, Enhanced Oxidative Stress Response, and Profound Acceleration in Response to Glycerol.

Exploration is a recently discovered mode of growth and behavior exhibited by some species that is distinct from their classical sporulating life cycle. While much has been uncovered regarding initiating environmental conditions and phenotypic outcomes of exploratory growth, how this process is coordinated at a genetic level remains unclear. We used RNA sequencing to survey global changes in the transcriptional profile of exploring cultures over time in the model organism Streptomyces venezuelae.

ClpP inhibitors are produced by a widespread family of bacterial gene clusters.

The caseinolytic protease (ClpP) is part of a highly conserved proteolytic complex whose disruption can lead to antibacterial activity but for which few specific inhibitors have been discovered. Specialized metabolites produced by bacteria have been shaped by evolution for specific functions, making them a potential source of selective ClpP inhibitors. Here, we describe a target-directed genome mining strategy for discovering ClpP-interacting compounds by searching for biosynthetic gene clusters that contain duplicated copies of ClpP as putative antibiotic resistance genes.

Three-Dimensional Structure and Optimization of the Metallo-β-Lactamase Inhibitor Aspergillomarasmine A.

The aminopolycarboxylic acid aspergillomarasmine A (AMA) is a natural Zn metallophore and inhibitor of metallo-β-lactamases (MBLs) which reverses β-lactam resistance. The first crystal structure of an AMA coordination complex is reported and reveals a pentadentate ligand with distorted octahedral geometry. We report the solid-phase synthesis of 23 novel analogs of AMA involving structural diversification of each subunit (l-Asp, l-APA1, and l-APA2).

Aerosol delivery, but not intramuscular injection, of adenovirus-vectored tuberculosis vaccine induces respiratory-mucosal immunity in humans.

BackgroundAdenovirus-vectored (Ad-vectored) vaccines are typically administered via i.m. injection to humans and are incapable of inducing respiratory mucosal immunity.

Prospects for Antibacterial Discovery and Development.

The rising prevalence of multidrug-resistant bacteria is an urgent health crisis that can only be countered through renewed investment in the discovery and development of antibiotics. There is no panacea for the antibacterial resistance crisis; instead, a multifaceted approach is called for. In this Perspective we make the case that, in the face of evolving clinical needs and enabling technologies, numerous validated antibacterial targets and associated lead molecules deserve a second look.

Demonstration of the role of cell wall homeostasis in growth and the action of bactericidal antibiotics.

Bacterial cell wall peptidoglycan is essential, maintaining both cellular integrity and morphology, in the face of internal turgor pressure. Peptidoglycan synthesis is important, as it is targeted by cell wall antibiotics, including methicillin and vancomycin. Here, we have used the major human pathogen to elucidate both the cell wall dynamic processes essential for growth (life) and the bactericidal effects of cell wall antibiotics (death) based on the principle of coordinated peptidoglycan synthesis and hydrolysis.

A non-reactive natural product precursor of the duocarmycin family has potent and selective antimalarial activity.

We identify a selective nanomolar inhibitor of blood-stage malarial proliferation from a screen of microbial natural product extracts. The responsible compound, PDE-I, is a precursor of the anticancer duocarmycin family that preserves the class's sequence-specific DNA binding but lacks its signature DNA alkylating cyclopropyl warhead. While less active than duocarmycin, PDE-I retains comparable antimalarial potency to chloroquine.

Profiling the Human Oral Mycobiome in Tissue and Saliva Using ITS2 DNA Metabarcoding Compared to a Fungal-Specific Database.

The advent of high-throughput sequencing has caused a paradigm shift from the one-pathogen one-disease model to the significance of dysbiosis of the oral microbiome, including the oral mycobiome. The oral mycobiome can be profiled by a method modified from that used to profile the bacteriome with 16S rRNA gene primers. The first modification is to include an initial fungus lysis step that ensures representative yields of fungal DNA.

Whole-Genome Sequencing of Pathogens in Saliva : A Target-Enrichment Approach for SARS-CoV-2.

Outbreak analysis and transmission surveillance of viruses can be performed via whole-genome sequencing after viral isolation. Such techniques have recently been applied to characterize and monitor SARS-CoV-2 , the etiological agent of the COVID-19 pandemic. However, the isolation and culture of SARS-CoV-2 is time consuming and requires biosafety level 3 containment, which is not ideal for many resource-constrained settings.