In-Vitro Antibacterial Activity of Curcumin-Loaded Nanofibers Based on Hyaluronic Acid against Multidrug-Resistant ESKAPE Pathogens

Bacterial infections have accompanied humanity throughout its history and became vitally important in the pandemic area. The most pathogenic bacteria are multidrug-resistant strains, which have become widespread due to their natural biological response to the use of antibiotics, including uncontrolled use. The current challenge is finding highly effective antibacterial agents of natural origin, which, however, have low solubility and consequently poor bioavailability. Curcumin, derived from Curcuma longa, is an example of a natural biologically active agent with a wide spectrum of biological effects, particularly against Gram-positive bacteria. However, curcumin exhibits extremely low antibacterial activity against Gram-negative bacteria. Curcumin’s hydrophobicity limits its use in medicine. As such, various polymeric systems have been used, especially biopolymer-based electrospun nanofibers. In the present study, the technological features of the fabrication of curcumin-loaded hyaluronic acid-based nanofibers are discussed in detail, their morphological characteristics, wettability, physico-chemical properties, and curcumin release profiles are demonstrated, and their antibacterial activity against multi-drug resistant ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are evaluated. It is noteworthy that the fibers containing a stable HA–curcumin complex showed high antibacterial activity against both Gram-positive and Gram-negative bacteria, which is an undeniable advantage. It is expected that the results of this work will contribute to the development of antibacterial drugs for topical and internal use with high efficacy and considerably lower side effects

Peptide-Based Biosensor for Express Diagnostics of Coronavirus Respiratory Infections

At the end of year 2019 the first reports appeared of a new coronavirus and on 31st December 2019 WHO declared a public health emergency of international concern. To date (as of 6:08 pm CET, 24th November 2020) according to WHO the new coronavirus, now called severe acute respiratory syndrome (SARS)-CoV-2, has infected 58,900,547 people and killed 1,393,305 people worldwide. It is extremely important to develop means for express diagnostics to ensure prompt action to limit the spread of infection. One of the diagnostic approaches, is the detection of viral particles in swabs. This approach can be realized using a biosensor with specific ligands, based on peptide molecules complementary to surface viral proteins. The concept of the so-called Systems of Conjugated Ionic-Hydrogen Bonds (abbreviated—SSIVS, CIHBS) implemented in the Protein-3D computer program, was applied to analyze the spatial structures of the bonds between the SARS-CoV-2 spike protein and the ACE-2 (Angiotensin converting enzyme 2) receptor, in order to reveal the perspective peptide sequences. There are two clearly marked areas of contact of the spike with the cell receptor—upper and lower, which are visualized in the SSIVS form, and the complex formed at this site is strong enough to ensure its attachment to the coronavirus spike and can compete for binding with the ACE-2 receptor. Two peptides were developed that form a spatial structure complementary to the coronavirus spike: of eight (No. one) and of 15 (No. two) amino acid residues. The peptides were covalently bound to biochip platforms via neutral linkers to form sites with peptides No. one and No. two. The third site has a neutral hydrophilic surface to serve as a reference. The platform was integrated with a microfluidic channel and was used as a flow through device. The detection of bound viral particles was carried out using UV excitation and direct registration of viral proteins fluorescence. The preliminary laboratory tests demonstrated the efficiency of the biosensor

External oxidant‐free and transition metal‐free synthesis of 5‐amino‐1,2,4‐thiadiazoles as promising antibacterials against ESKAPE pathogen strains

A new route to 5-amino-1,2,4-thiadiazole derivatives via reaction of N-chloroamidines with isothiocyanates has been proposed. The advantages of this method are high product yields (up to 93%), the column chromatography-free workup procedure, scalability and the absence of additive oxidizing agents or transition metal catalysts. The 28 examples of 5-amino-1,2,4thiadiazole derivatives obtaining via the proposing protocol were evaluated in vitro against ESKAPE pathogens strains (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter cloacae). It was found that compounds 5ba, 5bd, 6a, 6d and 6c have potent antibacterial activity (MIC values 0.09–1.5 μg mL−1), which is superior to the activity of commercial antibiotics such as pefloxacin (MIC 4–8 μg  mL−1) and streptomycin (MIC 2–32 μg  mL−1). The additional cytotoxic assay of hit compounds on PANC-1 cell line demonstrated the low or non-cytotoxicity activity at the same level of concentrations. Thus, these 5 compounds are promising starting point for further antimicrobial drug development

Mutually Isomeric 2- and 4-(3-Nitro-1,2,4-triazol-1-yl)pyrimidines Inspired by an Antimycobacterial Screening Hit: Synthesis and Biological Activity against the ESKAPE Panel of Pathogens

Starting from the structure of antimycobacterial screening hit OTB-021 which was devoid of activity against ESKAPE pathogens, we designed, synthesized and tested two mutually isomeric series of novel simplified analogs, 2- and 4-(3-nitro-1,2,4-triazol-1-yl)pyrimidines, bearing various amino side chains. These compounds demonstrated a reverse bioactivity profile being inactive against M. tuberculosis while inhibiting the growth of all ESKAPE pathogens (with variable potency patterns) except for Gram-negative P. aeruginosa. Reduction potentials (E1/2, V) measured for selected compounds by cyclic voltammetry were tightly grouped in the −1.3–−1.1 V range for a reversible single-electron reduction. No apparent correlation between the E1/2 values and the ESKAPE minimum inhibitory concentrations was established, suggesting possible significance of other factors, besides the compounds’ reduction potential, which determine the observed antibacterial activity. Generally, more negative E1/2 values were displayed by 2-(3-nitro-1,2,4-triazol-1-yl)pyrimidines, which is in line with the frequently observed activity loss on moving the 3-nitro-1,2,4-triazol-1-yl moiety from position 4 to position 2 of the pyrimidine nucleus

Non-natural 2H-azirine-2-carboxylic acids: an expedient synthesis and antimicrobial activity

Non-natural 2H-azirine-2-carboxylic acids were obtained in high yields by FeCl2-catalyzed isomerization of 5-chloroisoxazoles to azirine-2-carbonyl chlorides followed by their hydrolysis. The 3-aryl- and 3- heteroaryl-substituted acids are stable during prolonged storage, exhibit antibacterial activity against ESKAPE pathogens and show a low level of cytotoxicitythe Scientifc Council of the President of the Russian Federation (MK-2698.2019.3

Ancient genomes suggest the eastern Pontic-Caspian steppe as the source of western Iron Age nomads

For millennia, the Pontic-Caspian steppe was a connector between the Eurasian steppe and Europe. In this scene, multidirectional and sequential movements of different populations may have occurred, including those of the Eurasian steppe nomads. We sequenced 35 genomes (low to medium coverage) of Bronze Age individuals (Srubnaya-Alakulskaya) and Iron Age nomads (Cimmerians, Scythians, and Sarmatians) that represent four distinct cultural entities corresponding to the chronological sequence of cultural complexes in the region. Our results suggest that, despite genetic links among these peoples, no group can be considered a direct ancestor of the subsequent group. The nomadic populations were heterogeneous and carried genetic affinities with populations from several other regions including the Far East and the southern Urals. We found evidence of a stable shared genetic signature, making the eastern Pontic-Caspian steppe a likely source of western nomadic groups.Knut and Alice Wallenberg Foundation (1000 Ancient Genome Project) ; Riksbankens Jubileumsfond ; UPPMAX resources (Uppsala Multidisciplinary Centre for Advanced Computational Science)Publisher's Versio