Rapid luminescence-based screening method for SARS- CoV-2 inhibitors discovery.

The COVID-19 pandemic has emphasized the necessity for rapid and adaptable drug screening platforms against live pathogenic viruses that require high levels of biosafety containment. Conventional antiviral testing is time-consuming and labor-intensive. Here, we outline the design and validation of a semi-automated drug-screening platform for SARS-CoV-2 that utilizes multiple liquid handlers, a stable A549 cell line expressing ACE2 and TMPRSS2 receptors, and a recombinant SARS-CoV-2 strain harboring the nano-luciferase gene.

Small-molecule inhibition of SARS-CoV-2 NSP14 RNA cap methyltransferase.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The rapid development of highly effective vaccines against SARS-CoV-2 has altered the trajectory of the pandemic, and antiviral therapeutics have further reduced the number of COVID-19 hospitalizations and deaths. Coronaviruses are enveloped, positive-sense, single-stranded RNA viruses that encode various structural and non-structural proteins, including those critical for viral RNA replication and evasion from innate immunity.

A multidimensional assessment of in-host fitness costs of drug resistance in the opportunistic fungal pathogen Candida glabrata.

Drug-resistant microbes typically carry mutations in genes involved in critical cellular functions and may therefore be less fit under drug-free conditions than susceptible strains. Candida glabrata is a prevalent opportunistic yeast pathogen with a high rate of fluconazole resistance (FLZR), echinocandin resistance (ECR), and multidrug resistance (MDR) relative to other Candida. However, the fitness of C.

CTC-177, a novel drug-Fc conjugate, shows promise as an immunoprophylactic agent against multidrug-resistant Gram-negative bacterial infections.

Background: The widespread emergence of antibiotic resistance including MDR in Gram-negative bacterial pathogens poses a critical challenge to the current antimicrobial armamentarium.

Objectives: To create a novel drug-Fc conjugate (DFC) that can be delivered at sustained and prolonged levels while simultaneously activating the host immune response to combat MDR Gram-negative infections.

Methods: The Cloudbreak™ platform was used to develop DFCs consisting of a targeting moiety (TM) (a polymyxin-derived dimer) attached via a non-cleavable linker to an effector moiety (EM) (the Fc domain of human IgG1).

Novel Pan-Coronavirus 3CL Protease Inhibitor MK-7845: Biological and Pharmacological Profiling.

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) continues to be a global threat due to its ability to evolve and generate new subvariants, leading to new waves of infection. Additionally, other coronaviruses like Middle East respiratory syndrome coronavirus (MERS-CoV, formerly known as hCoV-EMC), which first emerged in 2012, persist and continue to present a threat of severe illness to humans. The continued identification of novel coronaviruses, coupled with the potential for genetic recombination between different strains, raises the possibility of new coronavirus clades of global concern emerging.

Correction: Jiménez-Ortigosa et al. Cryo-Electron Tomography of Plasma Membrane Proteins. 2021, , 120.

The authors wish to update the article title to "Cryo-Electron Tomography of Plasma Membrane Proteins" [...

Genes Modulating Echinocandin Susceptibility of Caspofungin-Adapted Mutants Are Constitutively Expressed in Clinical Isolates with Intermediate or Full Resistance to Echinocandins.

The opportunistic fungus is the leading cause of invasive candidiasis in immune-compromised individuals. Drugs from the echinocandin (ECN) class, including caspofungin, are used as a first line of therapy against invasive candidiasis. The only known mechanism of clinical resistance to ECNs is point mutations in the gene, which encodes the drug target.

Echinocandin persistence directly impacts the evolution of resistance and survival of the pathogenic fungus .

Unlabelled: Recent epidemiological studies documented an alarming increase in the prevalence of echinocandin-resistant (ECR) blood isolates. ECR isolates are known to arise from a minor subpopulation of a clonal population, termed echinocandin persisters. Although it is believed that isolates with a higher echinocandin persistence (ECP) are more likely to develop ECR, the implication of ECP needs to be better understood.

Invention of MK-7845, a SARS-CoV-2 3CL Protease Inhibitor Employing a Novel Difluorinated Glutamine Mimic.

As SARS-CoV-2 continues to circulate, antiviral treatments are needed to complement vaccines. The virus's main protease, 3CLPro, is an attractive drug target in part because it recognizes a unique cleavage site, which features a glutamine residue at the P1 position and is not utilized by human proteases. Herein, we report the invention of MK-7845, a novel reversible covalent 3CLPro inhibitor.

Humoral and cellular immune responses against SARS-CoV-2 post-vaccination in immunocompetent and immunocompromised cancer populations.

Unlabelled: Cancer patients are at risk for severe coronavirus disease 2019 (COVID-19) outcomes due to impaired immune responses. However, the immunogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is inadequately characterized in this population. We hypothesized that cancer vs non-cancer individuals would mount less robust humoral and/or cellular vaccine-induced immune SARS-CoV-2 responses.

Small Molecule Benzothiophene with Efficacy in a Mouse Model of Drug-Resistant Infection.

Hospital-acquired infections, caused by ESKAPE bacteria, are a challenging global public health concern, in part due to the emergence of drug-resistant strains. While profiling a diverse set of compounds for activity this class of bacteria, we noted that the benzothiophene JSF-2827 exhibited promising antibacterial activity against . A hit evolution campaign ensued, involving the design, synthesis, and biological assay of analogues designed to address early issues such as a short mouse liver microsome half-life and a modest mouse pharmacokinetic profile.

Fungicide-tolerant persister formation during cryptococcal pulmonary infection.

Bacterial persisters, a subpopulation of genetically susceptible cells that are normally dormant and tolerant to bactericides, have been studied extensively because of their clinical importance. In comparison, much less is known about the determinants underlying fungicide-tolerant fungal persister formation in vivo. Here, we report that during mouse lung infection, Cryptococcus neoformans forms persisters that are highly tolerant to amphotericin B (AmB), the standard of care for treating cryptococcosis.

Reactive oxidant species induced by antifungal drugs: identity, origins, functions, and connection to stress-induced cell death.

Reactive oxidant species (ROS) are unstable, highly reactive molecules that are produced by cells either as byproducts of metabolism or synthesized by specialized enzymes. ROS can be detrimental, e.g.

Overlooked petites are echinocandin tolerant, induce host inflammatory responses, and display poor fitness.

is a major fungal pathogen, which is able to lose mitochondria and form small and slow-growing colonies, called "petite." This attenuated growth rate has created controversies and questioned the clinical importance of petiteness. Herein, we have employed multiple omics technologies and mouse models to critically assess the clinical importance of petite phenotype.

In Vivo Antiviral Efficacy of LCTG-002, a Pooled, Purified Human Milk Secretory IgA product, Against SARS-CoV-2 in a Murine Model of COVID-19.

Immunoglobulin A (IgA) is the most abundant antibody (Ab) in human mucosal compartments including the respiratory tract, with the secretory form of IgA (sIgA) being dominant and uniquely stable in these environments. sIgA is naturally found in human milk, which could be considered a global resource for this biologic, justifying the development of human milk sIgA as a dedicated airway therapeutic for respiratory infections such as SARS-CoV-2. In the present study, methods were therefore developed to efficiently extract human milk sIgA from donors who were either immunologically naïve to SARS-CoV-2 (pooled as a control IgA) or had recovered from a PCR-confirmed SARS-CoV-2 infection that elicited high-titer anti-SARS-CoV-2 Spike sIgA Abs in their milk (pooled together to make LCTG-002).

Molecular and Clinical Epidemiology of SARS-CoV-2 Infection among Vaccinated and Unvaccinated Individuals in a Large Healthcare Organization from New Jersey.

New Jersey was among the first states impacted by the COVID-19 pandemic, with one of the highest overall death rates in the nation. Nevertheless, relatively few reports have been published focusing specifically on New Jersey. Here we report on molecular, clinical, and epidemiologic observations, from the largest healthcare network in the state, in a cohort of vaccinated and unvaccinated individuals with laboratory-confirmed SARS-CoV-2 infection.

[First experience of 3D-laparoscopy in donor nephrectomy].

Objective: To assess the first experience of 3D imaging for laparoscopic donor nephrectomy.

Material And Methods: The study included 28 laparoscopic donor nephrectomies and 28 subsequent transplantations to related recipients. Of these, 14 laparoscopic donor nephrectomies were performed using 3D camera.

Overlooked petites are echinocandin tolerant, induce host inflammatory responses, and display poor fitness.

Unlabelled: Small colony variants (SCVs) are relatively common among some bacterial species and are associated with poor prognosis and recalcitrant infections. Similarly, - a major intracellular fungal pathogen - produces small and slow-growing respiratory-deficient colonies, termed "petite." Despite reports of clinical petite .

Novel Non-Hot Spot Modification in Fks1 of Candida auris Confers Echinocandin Resistance.

We determined the echinocandin susceptibility and genotypes of 13 clinical isolates of Candida auris that were recovered from 4 patients at a tertiary care center in Salvador, Brazil. Three isolates were categorized as echinocandin-resistant, and they harbored a novel mutation that led to an amino acid change W691L located downstream from hot spot 1. When introduced to echinocandin-susceptible C.

Candida parapsilosis isolates carrying mutations outside FKS1 hotspot regions confer high echinocandin tolerance and facilitate the development of echinocandin resistance.

Candida parapsilosis is a significant cause of candidemia worldwide. Echinocandin-resistant (ECR) and echinocandin-tolerant (ECT) C. parapsilosis isolates have been reported in various countries but are rare.

Macrophage internalization creates a multidrug-tolerant fungal persister reservoir and facilitates the emergence of drug resistance.

Candida glabrata is a major fungal pathogen notable for causing recalcitrant infections, rapid emergence of drug-resistant strains, and its ability to survive and proliferate within macrophages. Resembling bacterial persisters, a subset of genetically drug-susceptible C. glabrata cells can survive lethal exposure to the fungicidal echinocandin drugs.