Electronic and Lattice Distortions Induce Elastic Softening in Refractory Multicomponent Borides.

Borides are extensively employed in applications demanding exceptionally high hardness, which arises from the unique and strong crystallographic arrangement of boron atoms therein. Addition of multiprincipal elements in borides is expected to enhance their structural properties due to lattice distortion and high configurational entropy. In contrast, we unravel a phenomenon of elastic softening in refractory multicomponent borides from first-principle predictions, which concur with experimentally determined metrics in their single-phase multiprincipal element counterparts. The reductions in the bulk and Young's modulus of these compounds are attributed to the lengthening and distortion of the boron-boron bonds and angles, but more critically to the perturbation in the charge densities arising from the different cations and the consequential increase in statistical weights of the d5 configuration states of the transition metals present in the boride..

Identification of Potential Antitubulin Agents with Anticancer Assets from a Series of Imidazo[1,2-a]quinoxaline Derivatives: In Silico and In Vitro Approaches.

Computer-aided drug design is a powerful and promising tool for drug design and development, with a reduced cost and time. In the current study, we rationally selected a library of 34 fused imidazo[1,2-a]quinoxaline derivatives and performed virtual screening, molecular docking, and molecular mechanics for a lead identification against tubulin as an anticancer molecule. The computational analysis and pharmacophoric features were represented as 1A2; this was a potential lead against tubulin, with a maximized affinity and binding score at the colchicine-binding site of tubulin. The efficiency of this lead molecule was further identified using an in vitro assay on a tubulin enzyme and the anticancer potential was established using an MTT assay. Compound 1A2 (IC50 = 4.33-6.11 µM against MCF-7, MDA-MB-231, HCT-116, and A549 cell lines) displayed encouraging results similar to the standard drug colchicine in these in vitro studies, which further confirmed the effectiveness of CADD in new drug developments. Thus, we successfully applied the utility of in silico techniques to identify the best plausible leads from the fused azaheterocycles.

Structural insight into substrate binding of Acinetobacter baumannii polyphosphate-AMP phosphotransferase (PPK2), a novel drug target.

Acinetobacter baumannii is an opportunistic pathogen known for high morbidity and mortality. It causes life-threatening infections, such as ventilator-associated pneumonia (VAP), bacteremia, meningitis, wound and urinary tract infections (UTI). Increase in carbapenem resistance exhibited by A. baumannii has accentuated the need for novel targets for effective treatment. Despite the pronounced relevance of PPK2 as a pathogenicity determinant in several pathogens, it has not been explored as a drug target in A. baumannii. The present study was piloted to investigate the substrate binding by A. baumannii PPK2 (AbPPK2), a two-domain Class II polyphosphate kinase 2. A homology model of AbPPK2 was developed and validated for molecular docking of ATP and ADP in the predicted binding pocket. Further analysis of AbPPK2 revealed a set of common residues in the catalytic cleft interacting with ATP and ADP which would be useful for the screening of inhibitors against A. baumannii.

Microaerobic conditions enhance laccase production from Rheinheimera sp. in an economical medium.

Statistical optimization of aeration conditions viz. aerobic, microaerobic and anaerobic, was performed using response surface methodology (RSM) utilizing soybean meal as medium to enhance the production of laccase from Rheinheimera sp. Maximum laccase yield (18.48 × 105 U/L) was obtained under microaerobic (static) conditions sustained for 12 h in tandem with 26 h aerobically (150 rpm) grown culture, which was 17.03-fold higher than laccase production in the starting M162 medium under aerobic conditions (150 rpm). The reduction in incubation time from 72 to 38 h and utilization of cost-effective soybean meal as medium, which is easily available from local market, have provided a promising, eco-friendly method of laccase enzyme production. Enhanced expression of laccase gene under microaerobic conditions corresponded to the increased expression of fnr (fumarate nitrate reductase) gene, the oxygen sensing global regulator. The putative FNR-binding site upstream of laccase transcription initiation site was predicted to play an imperative role in Rheinheimera sp. adaptation from aerobic to microaerobic conditions and for enhanced laccase production.

Improvement in Digestion Resistibility of Mandua Starch (Eleusine coracana) after Cross-Linking with Epichlorohydrin.

Starch, being a polymer of excessive demand for the development of products of pharmaceutical importance, has been tremendously treated in many ways for improving the desired characteristics such as viscosity, paste clarity, digestibility, swelling, syneresis, and so forth. In the present study, alkali-extracted starch of mandua grains (Eleusine coracana; family Poaceae) was treated with epichlorohydrin for cross-linking and the modified starch was assessed for swelling, solubility, water binding capacity, moisture content, and degree of cross-linking. The digestion resistibility of modified starch was analyzed in simulated gastric fluid (pH 1.2), simulated intestinal fluid (pH 6.8), and simulated colonic fluid (pH 7.4). The structural modifications in treated mandua starch were analyzed by Fourier transform infrared (FTIR) spectroscopy, powder X-ray diffraction (XRD), scanning electron microscopy, thermogravimetric analysis, and C13 nuclear magnetic resonance (13C NMR). The results of the study reflected the significant modification in mandua starch after treatment with epichlorohydrin (1.0% w/w sdb, solid dry basis). The degree of cross-linking of treated mandua starch was 85.15%, and the swelling capacity of mandua starch changed from 226.51 ± 2.175 to 103.14 ± 1.998% w/w after cross-linking with epichlorohydrin. A remarkable increment in digestion resistibility was observed in modified mandua starch. The XRD pattern and FTIR spectra revealed the presence of resistant starch after chemical modification. The decomposition pattern of modified mandua starch was also different from extracted mandua starch. All the results reflected the effective modification of mandua starch by epichlorohydrin and the formation of resistant starch to a significant content. The treated mandua starch may have the potential in developing various preparations of food, nutraceuticals, and pharmaceuticals.

3-indoleacetonitrile attenuates biofilm formation and enhances sensitivity to imipenem in Acinetobacter baumannii.

Acinetobacter baumannii poses a global danger due to its ability to resist most of the currently available antimicrobial agents. Furthermore, the rise of carbapenem-resistant A. baumannii isolates has limited the treatment options available. In the present study, plant auxin 3-indoleacetonitrile (3IAN) was found to inhibit biofilm formation and motility of A. baumannii at sublethal concentration. Mechanistically, 3IAN inhibited the synthesis of the quorum sensing signal 3-OH-C12-HSL by downregulating the expression of the abaI autoinducer synthase gene. 3IAN was found to reduce the minimum inhibitory concentration of A. baumannii ATCC 17978 against imipenem, ofloxacin, ciprofloxacin, tobramycin, and levofloxacin, and significantly decreased persistence against imipenem. Inhibition of efflux pumps by downregulating genes expression may be responsible for enhanced sensitivity and low persistence. 3IAN reduced the resistance to imipenem in carbapenem-resistant A. baumannii isolates by downregulating the expression of OXA ß-lactamases (blaoxa-51 and blaoxa-23), outer membrane protein carO, and transporter protein adeB. These findings demonstrate the therapeutic potential of 3IAN, which could be explored as an adjuvant with antibiotics for controlling A. baumannii infections.

Role of Antimicrobial Peptides in Treatment and Prevention of Mycobacterium Tuberculosis: A Review.

Tuberculosis (TB) is one of the leading cause of death worldwide, and the world is fighting with this global health emergency from the past 25 year. The current clinical interventions for the management of TB face a number of inherent challenges which includes low patient compliance due to the long therapy regimen, and emerging antimicrobial resistance. Therefore, there is an unmet need of new anti-TB therapeutic agent with enhanced safety profile, which can reduce the duration of therapy, enhanced bioavailability and efficacy against drug resistant forms of TB. Bacteriocins or anti microbial peptides (AMPs) occurring in microbes, human beings and other life forms have been investigated as host defense peptides. Structurally AMPs are short and ionized and play crucial role in innate immunity of host. Some AMPs can kill microbial infections directly while others function indirectly by altering the host defense mechanisms. Amidst rising issue of antibiotic resistance, AMPs are being tested in clinical research as potential antibiotics and novel therapeutics to fight against infections and non-infectious diseases. Studies have also highlighted the ability of AMPs to act against the bacteria spreading tuberculosis. The present review provides information on antimicrobial peptides, highlights their biological role, classification and mode of action in treatment and prevention of tuberculosis. It further mentions the prospects and challenges of developing peptides for their therapeutic applications against mycobacterium tuberculosis.

Chromenes - A Novel Class of Heterocyclic Compounds: Recent Advancements and Future Directions.

Chromenes are an important class of oxygen-containing heterocyclic compounds with intriguing biological activity, a simple structure with mild adverse effects. Chromenes are abundantly found in nature in the form of alkaloids, tocopherols, flavone, and anthocyanins. The Chromene nucleus is an important moiety for the discovery of new drug candidates. Chromene derivatives have shown various pharmacological activities like antiviral, anticancer, anti-inflammatory, antitumour, antimicrobial, antiproliferative, anticholinesterase, EPR-1 (Effector cell Protease Receptor-1) antagonist and MAO (Mono-Amine Oxidase) inhibitors. In SAR (Structure Activity Relationship) studies with chromene nucleus, it was found that 4-aryl moiety, 3-cyano group, and 2-amino group are essential for the cytotoxic activity. Substitution at the 7th position with electron donating group enhances the pharmacological activity whereas the electron withdrawing group decreases the pharmacological activity. Structural modifications at the chromene ring, middle aliphatic portion, and terminal aromatic ring yielded more potential 5-HT1A (5-Hydroxytryptamine 1A) receptor affinity and antidiabetic activity. Chromenes with cyclic secondary amine and 4-hydroxy phenyl substituents yielded potent antimicrobial compounds. This review summarizes the importance of chromenes in rational drug design and the development of novel molecules with a variety of pharmacological activities.

Vaccine development to control the rising scourge of antibiotic-resistant Acinetobacter baumannii: a systematic review.

Acinetobacter baumannii has emerged as one of major nosocomial pathogen and global emergence of multidrug-resistant strains has become a challenge for developing effective treatment options. A. baumannii has developed resistance to almost all the antibiotics viz. beta-lactams, carbapenems, tigecycline and now colistin, a last resort of antibiotics. The world is on the cusp of post antibiotic era and the evolution of multi-, extreme- and pan-drug-resistant A. baumannii strains is its obvious harbinger. Various combinations of antibiotics have been investigated but no successful treatment option is available. All these failed efforts have led researchers to develop and implement prophylactic vaccination for the prevention of infections caused by this pathogen. In this review, the advantages and disadvantages of active and passive immunization, the types of sub-unit and multi-component vaccine candidates investigated against A. baumannii viz. whole cell organism, outer membrane vesicles, outer membrane complexes, conjugate vaccines and sub-unit vaccines have been discussed. In addition, the benefits of Reverse vaccinology are emphasized here in which the potential vaccine candidates are predicted using bioinformatic online tools prior to in vivo validations.

Tobramycin Stress Induced Differential Gene Expression in Acinetobacter baumannii.

Acinetobacter baumannii is a multidrug-resistant bacteria responsible for nosocomial infections with significant fatality rates globally. Therapeutic failure and relapse of infection has been associated with persister cells formation which can also lead to resistance in A. baumannii. In the present study, we observed that A. baumannii ATCC 17978 in exponential phase survived lethal concentrations of amikacin, rifampicin and ciprofloxacin by generating persister cells but was unable to survive tobramycin treatment. The transcriptome of A. baumannii ATCC 17978 was analyzed following exposure to a high concentration of tobramycin (10 × MIC) for a short period of time to study the possible mechanisms responsible for lethality. Tobramycin reduced the expression of genes involved in energy production (nuoH, nuoN, nuoM, cydA, sucC), oxidative stress protection (tauD, cysD), and nutrition uptake (ompW) significantly. In addition, hemerythrin (non-heme di-iron oxygen-binding protein) was found to be the most downregulated gene in response to tobramycin which needs to be further studied for its role in susceptibility to antibiotics. Tobramycin upregulated the expression of genes that are mainly involved in stress response (leucine catabolism, DNA repair and HicAB toxin-antitoxin system). The differentially expressed genes highlighted in the study provided insight into the probable molecular mechanism of tobramycin-induced cell death and revealed some novel targets that can be explored further for their potential to control A. baumannii.

Engineering multifunctional enzymes for agro-biomass utilization.

Lignocellulosic biomass is a plentiful renewable resource that can be converted into a wide range of high-value-added industrial products. However, the complexity of its structural integrity is one of the major constraints and requires combinations of different fibrolytic enzymes for the cost-effective, industrially and environmentally feasible transformation. An interesting approach is constructing multifunctional enzymes, either in a single polypeptide or by joining multiple domains with linkers and performing diverse reactions simultaneously, in a single host. The production of such chimera proteins multiplies the advantages of different enzymatic reactions in a single setup, in lesser time, at lower production cost and with desirable and improved catalytic activities. This review embodies the various domain-tailoring and extracellular secretion strategies, possible solutions to their challenges, and efforts to experimentally connect different catalytic activities in a single host, as well as their applications.

Antibiotic residues in environment: antimicrobial resistance development, ecological risks, and bioremediation.

The overuse of antibiotics and their disposal without processing are leading the environment and its inhabitants towards a serious health emergency. There is abundance of diverse antibiotic resistance genes and bacteria in environment, which demands immediate attention for the effective removal of antibiotics. There are physical and chemical methods for removal, but the generation of toxic byproducts has directed the efforts towards bioremediation for eco-friendly and sustainable elimination of antibiotics from the environment. Various effective and reliable bioremediation approaches have been used, but still antibiotic residues pose a major global threat. Recent developments in molecular and synthetic biology might offer better solution for engineering of microbe-metabolite biodevices and development of novel strains endowed with desirable properties. This review summarizes the impact of antibiotics on environment, mechanisms of resistance development, and different bioremediation approaches.

Biochemical, genotoxic, histological and ultrastructural effects on liver and gills of fresh water fish Channa punctatus exposed to textile industry intermediate 2 ABS.

The study was planned to assess the acute toxicity of textile industry intermediate, 2 amino benzene sulfonate (2 ABS) through biochemical, genotoxic, histopathological and ultrastructural (SEM) analysis in liver and gills of fresh water fish Channa punctatus. The fish were subjected to two sublethal concentrations (2.83 mg/30 g b. w. and 5.66 mg/30 g b. w.) for 96 h. A significant (p ≤ 0.05) increment in the enzymatic activity of catalase (CAT), superoxide dismutase (SOD) and glutathione reductase (GR) was observed followed by decline on CAT-SOD after 96 h of exposure in both the tissues, whereas increment in malondialdehyde (MDA) levels were observed throughout the exposure period for both the concentrations. Comet assay also showed elevated tail length and % tail DNA throughout the exposure period, marking maximum damage after 96 h for both the tissues. Light microscopy divulged several anomalies including: infiltration of lymphocytes, sinusoidal dilations, necrosis, vacuolation in liver and secondary lamellae fusion, telangiectasia and epithelial uplifting in gills. The highest degree of tissue change (DTC) in liver (50.33 ± 0.88) and gill (42.33 ± 2.18) was recorded with the highest concentration after 96 h of exposure. Scanning electron microscopy (SEM) also reaffirmed several alterations in liver and gills of fish. The findings of the present study inflict changes in liver and gills, marking the interference of 2 ABS with the normal functioning by suppressing the enzymatic activity, accelerating the lipid peroxidation, enhancing DNA damage and by disrupting normal architecture of liver and gills, making it toxic towards the fish even at sub-lethal concentrations.

COVID-19 Diagnosis: Current and Future Techniques.

COVID-19 pandemic continues to be a global threat, affecting more than 200 countries/territories at both human and economic level. This necessitates the rapid development of highly reliable diagnostic methods in order to effectively and accurately diagnose the pathology to prevent the spread of COVID-19. Currently, RT-PCR is the most widely used method worldwide for SARS-CoV-2 detection. Serological assays are being used for sero-surveys of SARS-CoV-2 antibody prevalence in the community. Radiology imaging has been useful in the clinical diagnosis of COVID-19. These methods have their own limitations and there are continued efforts to develop easier, economic, highly sensitive and specific, point-of-care methods. Reverse transcription-loop mediated isothermal amplification (RT-LAMP), nucleic acid sequence-based amplification (NASBA), CRISPR-Cas-based detection, and digital PCR are such techniques being employed in research laboratories, with many awaiting diagnostic approval from competent authorities. This review highlights the rapidly expanding array of existing and in-development diagnostic tests/strategies that may be used to diagnose SARS-CoV-2 infection in both clinical and research settings.

Bisphenol A induced toxicity in blood cells of freshwater fish Channa punctatus after acute exposure.

The widespread use of bisphenol A (BPA) has led to its ubiquity in the natural environment. It is extensively incorporated into different industrial products and is associated with deleterious health effects on both public and wildlife. The current trial was conducted to determine the toxic potential of bisphenol A using various parameters viz haematological, biochemical, and cytological in freshwater fish Channa punctatus. For this purpose, fish were exposed to 1.81 mg/l (1/4 of LC50) and 3.81 mg/l (1/2 of LC50) of BPA along with positive (acetone) and negative controls (water) for 96 h. The blood samples were collected at 24, 48, 72, and 96 h post-exposure. Compared to the control group, fish after acute exposure to BPA showed a significant decrease in HB content, number of red blood cells, PCV values whereas a significant increase in WBCs count was recorded with an increase in the exposure period. Besides, oxidative stress (determined as malondialdehyde content) increased as BPA concentration increased. Further, the activity of different antioxidant enzymes like catalase, and superoxide dismutase decreased significantly after treatment. Results also showed significantly increased frequency of morphological alterations, nuclear changes, and increased DNA damage potential of BPA in red blood cells. Further structural analysis of erythrocytes in maximally damaged group using Scanning Electron Microscopy was performed. The study concludes that BPA exhibits genotoxic activity and oxidative stress could be one of the mechanisms leading to genetic toxicity.

Potential genes associated with survival of Acinetobacter baumannii under ciprofloxacin stress.

Acinetobacter baumannii is an opportunistic pathogen that has acquired resistance to all available drugs. The rise in multi-drug resistance in A. baumannii has been exacerbated by its ability to tolerate antibiotics due to the persister cells, which are phenotypic variants of normal cells that can survive various stress conditions, resulting in chronicity of infection. In the present study we observed that A. baumannii formed persister cells against lethal concentration of ciprofloxacin in exponential phase. The transcriptome of A. baumannii was analyzed after exposure to high concentration of ciprofloxacin (50X MIC) to determine the possible mechanisms of survival. Transcriptome analysis showed differential expression of 146 genes, of which 101 were up-regulated and 45 were down-regulated under ciprofloxacin stress. Differentially expressed genes that might be important for persistence against ciprofloxacin were involved in DNA repair, phenylacetic acid degradation, leucine catabolism, HicAB toxin-antitoxin system and ROS response (iron-sulfur clusters, hemerythrin-like metal binding and Kdp). recA, umuD and ddrR genes involved in SOS response were also up-regulated. Knockout of umuD showed significant decrease in persister cells formation while they were completely eradicated in recA mutant strain. The differentially expressed genes highlighted in the study merit further investigation as therapeutic targets for effective control of A. baumannii infections.

Mucoadhesive microspheres of glutaraldehyde crosslinked mucilage of Isabgol husk for sustained release of gliclazide.

Mucoadhesive microspheres have their own significant amongst the various sustained release drug delivery systems. The prolonged residence time of these delivery devices at drug absorption site results in steep concentration gradient and enhanced bioavailability. In this study, the mucilage of Isabgol husk was applied as polymeric backbone to develop gliclazide loaded microspheres by crosslinking with glutaraldehyde. The formulations were studied for surface morphology, swelling behavior, particle size, in vitro release, release kinetics, in vitro mucoadhesion and gamma scintigraphy in rabbits. The release of gliclazide from microspheres was controlled by swelling of crosslinked microspheres followed by diffusion. Gamma scintigraphic images acquired for microspheres retention in gastrointestinal track of rabbits indicated the residence of formulation upto 24 h after oral administration. Gliclazide retained its integrity in polymeric matrix of microspheres as observed by Fourier transform infrared spectroscopy, differential scanning calorimetry and powder X-ray diffractometry. The sustained release of gliclazide and prolonged retention of microspheres in gastrointestinal track disclosed the rationality of mucoadhesive Isabgol husk microspheres in controlling the hyperglycemia in diabetes.

Combination of colistin and tobramycin inhibits persistence of Acinetobacter baumannii by membrane hyperpolarization and down-regulation of efflux pumps.

Acinetobacter baumannii, a leading cause of nosocomial infections, is a serious health threat. Limited therapeutic options due to multi-drug resistance and tolerance due to persister cells have urged the scientific community to develop new strategies to combat infections caused by this pathogen effectively. Since combination antibiotic therapy is an attractive strategy, the effect of combinations of antibiotics, belonging to four classes, was investigated on eradication of persister cells in A. baumannii. Among the antibiotics included in the study, tobramycin-based combinations were found to be the most effective. Tobramycin, in combination with colistin or ciprofloxacin, eradicated persister cells in A. baumannii in late exponential and stationary phases of growth. Mechanistically, colistin facilitated the entry of tobramycin into cells by increasing membrane permeability and inducing hyperpolarization of the inner membrane accompanied by increase in ROS production. Expression of the genes encoding universal stress protein and efflux pumps was down-regulated in response to tobramycin and colistin, suggesting increased lethality of their combination that might be responsible for eradication of persister cells. Thus, a combination of tobramycin and colistin could be explored as a promising option for preventing the relapse of A. baumannii infections due to persister cells.

Attenuation of Acinetobacter baumannii virulence by inhibition of polyphosphate kinase 1 with repurposed drugs.

Acinetobacter baumannii is clinically one of the most significant pathogens, especially in intensive care settings, because of its multidrug-resistance (MDR). Repurposing of high-affinity drugs is a faster and more plausible approach for combating the emergence of MDR and to tackle bacterial infections. This study was aimed to evaluate the approved drugs potentially inhibiting A. baumannii PPK1 (AbPPK1) mediated synthesis of polyphosphates (polyP). Based on virtual screening, molecular dynamic simulation, and CD spectroscopy for thermal stability, two stable ligands, etoposide and genistein, were found with promising contours for further investigation. Following in vitro inhibition of AbPPK1, the efficacy of selected drugs was further tested against virulence traits of A. baumannii. These drugs significantly reduced the biofilm formation, surface motility in A. baumannii and led to decreased survival under desiccation. In addition to inhibition of PPK1, both drugs increased the expression of polyP degrading enzyme, exopolyphosphatase (PPX), that might be responsible for the decrease in the total cellular polyP. Since polyP modulates the virulence factors in bacteria, destabilization of the polyP pool by these drugs seems particularly striking for their therapeutic applications against A. baumannii.