Notes

Stopping regarding Antihypertensive Drugs for the Result of Hospitalized Patients Together with Serious Intense Respiratory Syndrome-Coronavirus 2.
Microbial lipids play a critical role in the pathogenesis of infectious diseases by modulating the host cell membrane properties, including lipid/protein diffusion and membrane organization. Mycobacterium tuberculosis (Mtb) synthesizes various chemically distinct lipids that are exposed on its outer membrane and interact with host cell membranes. Rituximab manufacturer However, the effects of the structurally diverse Mtb lipids on the host cell membrane properties to fine-tune the host cellular response remain unknown. In this study, we employed membrane biophysics and cell biology to assess the effects of different Mtb lipids on cell membrane mechanics, lipid diffusion, and the cytoskeleton of THP-1 macrophages. We found that Mtb lipids modulate macrophage membrane properties, actin cytoskeleton, and biochemical processes, such as protein phosphorylation and lipid peroxidation, in a virulence lipid-selective manner. These results emphasize that Mtb can fine-tune its interactions with the host cells governed by modulating the lipid profile on its surface. These observations provide a novel lipid-centric paradigm of Mtb pathogenesis that is amenable to pharmacological inhibition and could promote the development of robust biomarkers of Mtb infection and pathogenesis.Cytotoxic frog antimicrobial peptide Temporin L (TempL) is an attractive molecule for the design of lead antimicrobial agents due to its short size and versatile biological activities. However, noncytotoxic TempL variants with desirable biological activities have rarely been reported. TempL analogue Q3K,TempL is water-soluble and possesses a significant antiendotoxin property along with comparable cytotoxicity to TempL. A phenylalanine residue, located at the hydrophobic face of Q3K,TempL and the "d" position of its phenylalanine zipper sequence, was replaced with a cationic lysine residue. This analogue, Q3K,F8K,TempL, showed reduced hydrophobic moment and was noncytotoxic with lower antimicrobial activity. Interestingly, swapping between tryptophan at the fourth and serine at the sixth positions turned Q3K,F8K,TempL totally amphipathic as reflected by its helical wheel projection with clusters of hydrophobic and hydrophilic residues and the highest hydrophobic moment among these peptides. Surprisingly, this analogue, SW,Q3K,F8K,TempL, was as noncytotoxic as Q3K,F8K,TempL but showed augmented antimicrobial and antiendotoxin properties, comparable to that of TempL and Q3K,TempL. SW,Q3K,F8K,TempL exhibited appreciable survival of mice against P. aeruginosa infection and a lipopolysaccharide (LPS) challenge. Unlike TempL and Q3K,TempL, SW,Q3K,F8K,TempL adopted an unordered secondary structure in bacterial membrane mimetic lipid vesicles and did not permeabilize them or depolarize the bacterial membrane. Overall, the results demonstrate the design of a nontoxic TempL analogue that possesses clusters of hydrophobic and hydrophilic residues with impaired secondary structure and shows a nonmembrane-lytic mechanism and in vivo antiendotoxin and antimicrobial activities. This paradigm of design of antimicrobial peptide with clusters of hydrophobic and hydrophilic residues and high hydrophobic moment but low secondary structure could be attempted further.Praziquantel is the only widely available drug to treat schistosomiasis. With very few candidates currently in the drug development pipeline, there is an urgent need to discover and develop novel antischistosomal drugs. In this regard, the pyrido[1,2-a]benzimidazole (PBI) scaffold has emerged as a promising chemotype in hit-to-lead efforts. Here, we report a novel series of antischistosomal PBIs with potent in vitro activity (IC50 values of 0.08-1.43 μM) against Schistosoma mansoni newly transformed schistosomula and adult worms. Moreover, the current PBIs demonstrated good hepatic microsomal stability (>70% of drug remaining after 30 min) and were nontoxic to the Chinese hamster ovarian and human liver HepG2 cells, though toxicity (selectivity index, SI less then 10) against the rat L6 myoblast cell line was observed. The compounds showed a small therapeutic window but were efficacious in vivo, exhibiting moderate to high worm burden reductions of 35.8-89.6% in S. mansoni-infected mice.The discovery of novel drug candidates with anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) potential is critical for the control of the global COVID-19 pandemic. Artemisinin, an old antimalarial drug derived from Chinese herbs, has saved millions of lives. Artemisinins are a cluster of artemisinin-related drugs developed for the treatment of malaria and have been reported to have multiple pharmacological activities, including anticancer, antiviral, and immune modulation. Considering the reported broad-spectrum antiviral potential of artemisinins, researchers are interested in whether they could be used to combat COVID-19. We systematically evaluated the anti-SARS-CoV-2 activities of nine artemisinin-related compounds in vitro and carried out a time-of-drug-addition assay to explore their antiviral mode of action. Finally, a pharmacokinetic prediction model was established to predict the therapeutic potential of selected compounds against COVID-19. Arteannuin B showed the highest anti-SARS-CoV-2 potential with an EC50 of 10.28 ± 1.12 μM. Artesunate and dihydroartemisinin showed similar EC50 values of 12.98 ± 5.30 μM and 13.31 ± 1.24 μM, respectively, which could be clinically achieved in plasma after intravenous administration. Interestingly, although an EC50 of 23.17 ± 3.22 μM was not prominent among the tested compounds, lumefantrine showed therapeutic promise due to high plasma and lung drug concentrations after multiple dosing. Further mode of action analysis revealed that arteannuin B and lumefantrine acted at the post-entry step of SARS-CoV-2 infection. This research highlights the anti-SARS-CoV-2 potential of artemisinins and provides leading candidates for anti-SARS-CoV-2 drug research and development.Colistin is an antibiotic of last resort used to treat infections caused by multidrug-resistant Gram-negative bacterial pathogens. The recent surge in reported cases of colistin-resistant infections urgently calls for fast and reliable diagnostic methods, which can be used for the facile detection and proper treatment of these challenging infections. A major mechanism of colistin resistance involves phosphoethanolamine (PE) modification of lipopolysaccharide (LPS), the molecular target of colistin. This LPS modification mechanism has been recently reported to be transferrable via a plasmid-carried mcr-1 gene, which is particularly concerning as it may readily confer colistin resistance to a wide array of bacterial pathogens. To develop molecular tools to allow facile detection of colistin resistance, we have herein enlisted a novel phage library that incorporates dynamic covalent warheads to recognize PE modifications on bacterial cells. Screening of this chemically modified phage library against colistin-resistant pathogens revealed a number of peptide probes that readily differentiate colistin-resistant bacterial strains from their colistin-susceptible counterparts.
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