Integrative analysis discovers Imidurea as dual multitargeted inhibitor of CD69, CD40, SHP2, lysozyme, GATA3, cCBL, and S-cysteinase from SARS-CoV-2 and M. tuberculosis.

Two of the deadliest infectious diseases, COVID-19 and tuberculosis (TB), have combined to establish a worldwide pandemic, wreaking havoc on economies and claiming countless lives. The optimised, multitargeted medications may diminish resistance and counter them together. Based on computational expression studies, 183 genes were co-expressed in COVID-19 and TB blood samples. We used the multisampling screening algorithms on the top ten co-expressed genes (CD40, SHP2, Lysozyme, GATA3, cCBL, SIVmac239 Nef, CD69, S-adenosylhomocysteinase, Chemokine Receptor-7, and Membrane Protein). Imidurea is a multitargeted inhibitor for COVID-19 and TB, as confirmed by extensive screening and post-filtering utilising MM\GBSA algorithms. Imidurea has shown docking and MM\GBSA scores of -8.21 to -4.75 Kcal/mol and -64.16 to -29.38 Kcal/mol, respectively. The DFT, pharmacokinetics, and interaction patterns suggest that Imidurea may be a drug candidate, and all ten complexes were tested for stability and bond strength using 100 ns for all MD atoms. The modelling findings showed the complex's repurposing potential, with a cumulative deviation and fluctuation of <2 Å and significant intermolecular interaction, which validated the possibilities. Finally, an inhibition test was performed to confirm our in-silico findings on SARS-CoV-2 Delta variant infection, which was suppressed by adding imidurea to Vero E6 cells after infection.

Gallic Acid Derived 1, 2-Diarylindole as a Potential Antifungal Agent against Candida Strain.

BACKGROUND: In recent decades, Candida albicans has become a serious issue for public health. The worldwide rapid rise in drug resistance to conventional therapies is the main contributing reason. Moreover, because of their potent activity at low concentrations and apparent lack of toxicity, compounds originating from plants are used in therapeutic treatments because of their potent activity at low concentrations and apparent lack of toxicity. Particularly in immunocompromised people, Candida species can result in a wide range of ailments. OBJECTIVES: Present manuscript describes antifungal activity of an indole derivative 1-(4-((5- methoxy-2-(3,4,5-trimethoxyphenyl)-1H-indol-1-yl) methyl) phenoxy)-N,N-dimethylethan-1- amine (7, 100DL-6) by using an in-silico and in-vitro anti-candidal activity against two Candida strains; Candida kefyr-DS-02 (ATCC-204093) and Candida albicans (AI-clinical isolate, AIIMS- Delhi). METHODS: The synthetic strategy for the preparation of indole derivatives was modified through Fischer indole reaction. Antifungal activity of an indole derivative 1-(4-((5-methoxy-2-(3,4,5- trimethoxyphenyl)-1H-indol-1-yl) methyl) phenoxy)-N,N-dimethylethan-1-amine (7, 100DL-6) was done by using an in-silico and in-vitro anti-candidal activity against two Candida strains; Candida kefyr-DS-02 (ATCC-204093) and Candida albicans (AI-clinical isolate, AIIMS-Delhi). Compound 100DL-6 efficacy was determined by Combination synergy study, ergosterol binding assay, MTT toxicity study and Mutagenicity. RESULTS: Compound 100DL-6 was obtained in 65% yield on desired motifs. Docking scores found were 100DL-6 (-8.7 kcal/mol) and Fluconazole (-7.6 kcal/mol). Further, RMSD were shown for 100DL6 (0.26 ± 0.23 nm) and fluconazole (1.2 ± 0.62 nm). Indole derivative 100DL-6 was active against the tested fungal pathogens and the total zone of inhibition was measured between 13-14 mm in diameter and MIC values between 31.25 µg/mL to 250 µg/mL and MFC values between 62.5 µg/mL to 500 µg/mL. In checkerboard assay synergistic mode of interaction of 100DL-6 with known antifungal drugs was observed. In the presence of ergosterol 100DL-6 and standard drug (s) increased their MIC values, demonstrating a considerable affinity for ergosterol. Compound 100DL-6 was considered to be less-cytotoxic to the cells as determined by MTT assay. Lead compound 100DL-6 was found to be non-mutagenic. CONCLUSION: In the present study, 100DL6 (indole derivatives) significantly abrupted the ergosterol biosynthetic pathway and showed moderate anti-candidal effects. These studies suggest that 100DL6 significantly enhances antifungal effect of clinical drug fluconazole synergistically and may be considered as in clinical trial prior to some extensive in-vivo validations.

Multisampling-based docking reveals Imidazolidinyl urea as a multitargeted inhibitor for lung cancer: an optimisation followed multi-simulation and in-vitro study.

Lung Cancer is one of the deadliest cancers, responsible for more than 1.80 million deaths annually worldwide, and it is on the priority list of WHO. In the current scenario, when cancer cells become resistant to the drug, making it less effective leaves the patient in vulnerable conditions. To overcome this situation, researchers are constantly working on new drugs and medications that can help fight drug resistance and improve patients' outcomes. In this study, we have taken five main proteins of lung cancer, namely RSK4 N-terminal kinase, guanylate kinase, cyclin-dependent kinase 2, kinase CK2 holoenzyme, tumour necrosis factor-alpha and screened the prepared Drug Bank library with 1,55,888 compounds against all using three Glide-based docking algorithms namely HTVS, standard precision and extra precise with a docking score ranging from -5.422 to -8.432 Kcal/mol. The poses were filtered with the MM\GBSA calculations, which helped to identify Imidazolidinyl urea C11H16N8O8 (DB14075) as a multitargeted inhibitor for lung cancer, validated with advanced computations like ADMET, interaction pattern fingerprints, and optimised the compound with Jaguar, producing satisfied relative energy. All five complexes were performed with MD Simulation for 100 ns with NPT ensemble class, producing cumulative deviation and fluctuations < 2 Å and a web of intermolecular interaction, making the complexes stable. Further, the in-vitro analysis for morphological imaging, Annexin V/PI FACS assay, ROS and MMP analysis caspase3//7 activity were performed on the A549 cell line producing promising results and can be an option to treat lung cancer at a significantly cheaper state.Communicated by Ramaswamy H. Sarma.

Computational screening and MM/GBSA-based MD simulation studies reveal the high binding potential of FDA-approved drugs against Cutibacterium acnes sialidase.

Cutibacterium acnes is an opportunistic pathogen linked with acne vulgaris, affecting 80-90% of teenagers globally. On the leukocyte (WBCs) cell surface, the cell wall anchored sialidase in C. acnes virulence factor, catalysing the sialoconjugates into sialic acids and nutrients for C. acnes resulting in human skin inflammation. The clinical use of antibiotics for acne treatments has severe adverse effects, including microbial dysbiosis and resistance. Therefore, identifying inhibitors for primary virulence factors (Sialidase) was done using molecular docking of 1030 FDA-approved drugs. Initially, based on binding energies (ΔG), Naloxone (ZINC000000389747), Fenoldopam (ZINC000022116608), Labetalol (ZINC000000403010) and Thalitone (ZINC000000057255) were identified that showed high binding energies as -10.2, -10.1, -9.9 and -9.8 kcal/mol, respectively. In 2D analysis, these drugs also showed considerable structural conformer of hydrogen and hydrophobic interactions. Further, a 100 ns MD simulation study found the lowest deviation and fluctuations with various intermolecular interactions to stabilise the complexes. Out of 4, the Naloxone molecule showed robust, steady, and stable RMSD 0.23 ± 0.18 nm. Further, MMGBSA analysis supports MD results and found strong binding energy (ΔG) -29.71 ± 4.97 kcal/mol. In Comparative studies with Neu5Ac2en (native substrate) revealed naloxone has a higher affinity for sialidase. The PCA analysis showed that Naloxone and Thalitone were actively located on the active site, and other compounds were flickered. Our extensive computational and statistical report demonstrates that these FDA drugs can be validated as potential sialidase inhibitors.Communicated by Ramaswamy H. Sarma.

inPhocus: Current State and Challenges of Phage Research in Singapore.

Bacteriophages and phage-derived proteins are a promising class of antibacterial agents that experience a growing worldwide interest. To map ongoing phage research in Singapore and neighboring countries, Lee Kong Chian School of Medicine, Nanyang Technological University Singapore (NTU) and Yong Loo Lin School of Medicine, National University of Singapore (NUS) recently co-organized a virtual symposium on Bacteriophage and Bacteriophage-Derived Technologies, which was attended by more than 80 participants. Topics were discussed relating to phage life cycles, diversity, the roles of phages in biofilms and the human gut microbiome, engineered phage lysins to combat polymicrobial infections in wounds, and the challenges and prospects of clinical phage therapy. This perspective summarizes major points discussed during the symposium and new perceptions that emerged after the panel discussion.

Therapeutic Applications of Self-assembled Indole-3-butanoyl-polyethylenimine Nanostructures.

This study demonstrates the therapeutic potential of indole-3-butanoyl-polyethylenimine (IBP) nanostructures formed via self-assembly in aqueous system. Dynamic light scattering (DLS) analysis confirmed the formation of the nanostructures in the size range of ~ 194-331 nm. These nanostructures showed commendable antimicrobial activity against wide range of microbes including multi-drug resistant bacteria. Besides, appreciable antioxidant and anti-inflammatory activities were also observed. Results of cytotoxicity studies, performed on normal transformed human embryonic kidney (HEK 293) cells and human red blood cells (hRBCs), revealed almost non-toxic behavior of these nanostructures, however, remarkable toxicity on human breast cancer cells (MCF-7), human osteosarcoma cells (Mg63) and human liver cancer cells (HepG2) was observed. The pre-apoptotic and anti-proliferative activity of IBP nanostructures were confirmed by acridine orange/propidium iodide dual staining assay followed by confocal microscopy and scratch assay on Mg63 cells. Taken together, these results advocate the promising potential of the synthesized IBP nanostructures in the therapeutic applications. Supplementary Information: The online version contains supplementary material available at 10.1007/s12088-022-01015-y.

Identification of natural inhibitors to inhibit C. acnes lipase through docking and simulation studies.

Acne vulgaris is a common skin disease affecting 80-90% of teenagers worldwide. C. acnes producing lipases are the main virulence factor that catalyzes sebum lipid into free fatty acid that is used for C. acnes growth. Recently, computational biology and bioinformatics play a significant role in drug discovery programs and the identification of novel lead(s). In this study, potential inhibitors against the C. acnes lipase have been identified via cost-effective computational investigations. Molecular docking, MD simulations, and binding affinity analysis have been performed between the active site of C. acnes lipase protein and selected natural plant constituents. First, C. acnes lipase protein was downloaded from PDB and defined the catalytically active site. Next, 16 active natural plant constituents were shortlisted from the PubChem library (based on their pharmacokinetics, pharmacodynamics, and antibacterial activity). Docking studies identified the best five active compounds that showed significantly strong binding affinity interacted through hydrogen bonding, hydrophobic interactions, and π-stacking with the active site residues of the target protein. Furthermore, a 100 ns MD simulation run showed a stable RMSD and less fluctuating RMSF graph for luteolin and neryl acetate. In silico investigation suggested that luteolin, neryl acetate, and isotretinoin were involved in stable interactions which were maintained throughout the MD run with the C. acnes lipase enzyme, virtually. The results advocated that these could potentially inhibit lipase activity and be used in the clinical management of acne.

Nanobiotics against antimicrobial resistance: harnessing the power of nanoscale materials and technologies.

Given the spasmodic increment in antimicrobial resistance (AMR), world is on the verge of "post-antibiotic era". It is anticipated that current SARS-CoV2 pandemic would worsen the situation in future, mainly due to the lack of new/next generation of antimicrobials. In this context, nanoscale materials with antimicrobial potential have a great promise to treat deadly pathogens. These functional materials are uniquely positioned to effectively interfere with the bacterial systems and augment biofilm penetration. Most importantly, the core substance, surface chemistry, shape, and size of nanomaterials define their efficacy while avoiding the development of AMR. Here, we review the mechanisms of AMR and emerging applications of nanoscale functional materials as an excellent substitute for conventional antibiotics. We discuss the potential, promises, challenges and prospects of nanobiotics to combat AMR.

Nano-Therapeutics to Treat Acne Vulgaris.

Nanotechnology is a novel approach to dermatologic treatment. Nanomaterials are materials typically defined as less than 100 nm in size. As this size approaches molecular dimensions, the chemical and physical properties vastly change due to a relative increase in surface area to volume  ratio. Unique and altered properties ensue, such as carbon becoming an electrical conductant in the nano form, and glass becoming a liquid. The interaction of nanoparticles with biota likewise changes. Novel therapeutics may be possible with the use of nanomaterials. Advantages of nanoparticles include the ability to overcome microbial resistance and potentially induce immunomodulatory effects. Engineered nanomaterials or the development of nano-therapeutics with photo-induced antibacterial propensity and immunomodulatory activities has the potential to open new prospects for the treatment of ubiquitous cutaneous diseases, such as acne vulgaris.

Polydopamine -aminoglycoside nanoconjugates: Synthesis, characterization, antimicrobial evaluation and cytocompatibility.

Development of nanoparticle- and self-assembled nanomaterial-based therapeutics has become a rapidly growing area in the field of nanotechnology. One of the natural compounds, dopamine, presents as a neurotransmitter in the human brain serving as a messenger and deals with the behavioural responses, has provided an ideal platform through self-polymerization under aerobic conditions leading to the formation of a beneficial organic biopolymer, polydopamine (PDA). This polymer provides sufficient reactive functionalities, which can further be use to attach amine- or thiol-containing ligands to obtain conjugates. In the present study, self-polymerized polydopamine nanoparticles have been synthesized and tethered to aminoglycosides (AGs: Gentamicin, Kanamycin and Neomycin) through amino moieties to obtain PDA-AG nanoconjugates. These nanoconjugates are characterized by physicochemical techniques and evaluated for their antimicrobial potency against various bacterial strains including resistant ones. Simultaneously, cytocompatibility was also assessed for PDA-AG nanoconjugates. Of these three nanoconjugates (PDA-Gentamicin, PDA-Kanamycin and PDA-Neomycin), PDA-Kanamycin (PDA-K) nanoconjugate exhibited the highest activity against potent pathogens, least toxicity in human embryonic kidney (HEK 293) cells and intense toxic effects on human glioblastoma (U87) cells. Together, these results advocate the promising potential of these nanoconjugates to be used as potent antimicrobials in future applications.

An Indian Desert Shrub 'Hiran Chabba', Farsetia hamiltonii Royle, Exhibits Potent Antioxidant and Hepatoprotective Effect Against Iron- Overload Induced Liver Toxicity in Swiss Albino Mice.

BACKGROUND: Farsetia hamiltonii Royle, also known as Hiran Chabba grows in desert regions. It is widely used as folk medicine to treat joint pains, diarrhea and diabetes. However, its antioxidant and iron chelation abilities both in vitro and in vivo have not yet been investigated. METHODS: The 70% methanolic extract of F. hamiltonii (FHME) was investigated for its free radical scavenging and iron chelation potential, in vitro. An iron-overload situation was established by intraperitoneal injection of iron-dextran in Swiss albino mice, followed by oral administration of FHME. Liver damage and serum parameters due to iron-overload were measured biochemically and histopathologically to test iron-overload remediation and hepatoprotective potential of FHME. Phytochemical analyses were performed to determine its probable bioactive components. RESULTS: FHME showed promising antioxidant activity, scavenged various reactive oxygen and nitrogen species and chelated iron in vitro. FHME reduced liver iron, serum ferritin, normalized serum parameters, reduced oxidative stress in liver, serum and improved liver antioxidant status in ironoverloaded mice. It also alleviated liver damage and fibrosis as evident from biochemical parameters and morphological analysis of liver sections. The phytochemical analyses of FHME reflected the presence of alkaloids, phenols, flavonoids and tannins. HPLC analysis indicated presence of tannic acid, quercetin, methyl gallate, catechin, reserpine, ascorbic acid and gallic acid. CONCLUSION: Based on the experimental outcome, FHME, an ethnologically important plant can be envisaged as excellent antioxidant and iron chelator drug capable of remediating iron-overload induced hepatotoxicity and the bioactive compounds present in FHME might be responsible for its efficacy.

Melanogenesis Inhibitors.

Abnormally high production of melanin or melanogenesis in skin melanocytes results in hyperpigmentation disorders, such as melasma, senile lentigines or freckles. These hyperpigmentary skin disorders can significantly impact an individual's appearance, and may cause emotional and psychological distress and reduced quality of life. A large number of melanogenesis inhibitors have been developed, but most have unwanted side-effects. Further research is needed to better understand the mechanisms of hyperpigmentary skin disorders and to develop potent and safe inhibitors of melanogenesis. This review summarizes the current understanding of melanogenesis regulatory pathways, the potential involvement of the immune system, various drugs in current use, and emerging treatment strategies to suppress melanogenesis.

Zinc Oxide Nanoparticles Dispersed in Ionic Liquids Show High Antimicrobial Efficacy to Skin-Specific Bacteria.

Zinc oxide (ZnO) nanoparticles have been shown in the literature to have antibacterial properties and have been widely used in antibacterial formulations. However, one of the problems with ZnO nanoparticles is their tendency to aggregate, thereby causing damage to normal cells and lowering their antibacterial efficacy during application. In this work, we have attempted to avoid this by using a combination of ZnO nanoparticles and ionic liquids, a class of low melting salts containing organic cations and organic/inorganic anions that show antibacterial property as well, and tested the antibacterial activity of this dispersion. ZnO nanoparticles of 60 nm were dispersed in two different ionic liquids-choline acetate (IL1) and 1-butyl-3-methylimidazolium chloride (IL2)-to achieve high dispersibility, whereas ZnO dispersed in phosphate-buffered saline was taken as a control. These dispersions were tested on four strains- Escherichia coli, Bacillus subtilis, Klebsiella pneumoniae, and Staphylococcus epidermidis. Maximum efficiency was obtained for ZnO nanoparticles dispersed in imidazolium-based ionic liquids against skin-specific S. epidermidis. Skin infections induced by S. epidermidis are prevalent in hospital-acquired diseases. In most cases, traditional antibiotic-based therapies fail to combat such infections. Our strategy of developing a dispersion of ZnO nanoparticles in ionic liquids shows superior antibacterial efficacy in comparison to that shown individually by ZnO nanoparticles or ionic liquids. We have also established that the mechanism of killing this skin-specific bacterium is possibly through the production of reactive oxygen species leading to bacterial cell lysis. Further, we showed that this formulation is biocompatible and nontoxic to normal keratinocyte cells even under coculture conditions.

Antimicrobial Efficacy of Synthetic Pyranochromenones and (Coumarinyloxy)acetamides.

Four (1, 2, 4 and 6) synthetic quaternary ammonium derivatives of pyranochromenones and (coumarinyloxy)acetamides were synthesized and investigated for their antimicrobial efficacy on MRSA (Methicillin-resistant Staphylococcus aureus), and multi-drug resistant Pseudomonas aeruginosa, Salmonella enteritidis and Mycobacterium tuberculosis H37Rv strain. One of the four compounds screened i.e. N,N,N-triethyl-10-((4,8,8-trimethyl-2-oxo-2,6,7,8-tetrahydropyrano[3,2-g]chromen-10-yl)oxy)decan-1-aminium bromide (1), demonstrated significant activity against S. aureus, P. aeruginosa and M. tuberculosis with MIC value of 16, 35, and 15.62 µg/ml respectively. The cytotoxicity evaluation of compound 1 on A549 cell lines showed it to be a safe antimicrobial molecule, TEM study suggested that the compound led to the rupture of the bacterial cell walls.

Multifunctional biosynthesized silver nanoparticles exhibiting excellent antimicrobial potential against multi-drug resistant microbes along with remarkable anticancerous properties.

This study demonstrates the therapeutic potential of silver nanoparticles (AgNPs), which were biosynthesized using the extracts of Citrus maxima plant. Characterization through UV-Vis spectrophotometry, Dynamic Light Scattering (DLS), Fourier Transform Infrared spectroscopy (FTIR), X-ray Diffraction (XRD) and Transmission Electron Microscopy (TEM) confirmed the formation of AgNps in nano-size range. These nanoparticles exhibited enhanced antioxidative activity and showed commendable antimicrobial activity against wide range of microbes including multi-drug resistant bacteria that were later confirmed by TEM. These particles exhibited minimal toxicity when cytotoxicity study was performed on normal human lung fibroblast cell line as well as human red blood cells. It was quite noteworthy that these particles showed remarkable cytotoxicity on human fibrosarcoma and mouse melanoma cell line (B16-F10). Additionally, the apoptotic topographies of B16-F10 cells treated with AgNps were confirmed by using acridine orange and ethidium bromide dual dye staining, caspase-3 assay, DNA fragmentation assay followed by cell cycle analysis using fluorescence-activated cell sorting. Taken together, these results advocate promising potential of the biosynthesized AgNps for their use in therapeutic applications.

Acetamide Derivatives of Chromen-2-ones as Potent Cholinesterase Inhibitors.

Alzheimer's disease (AD), a neurodegenerative disorder, is a serious medical issue worldwide with drastic social consequences. Inhibition of cholinesterase is one of the rational and effective approaches to retard the symptoms of AD and, hence, consistent efforts are being made to develop efficient anti-cholinesterase agents. In pursuit of this, a series of 19 acetamide derivatives of chromen-2-ones were synthesized and evaluated for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory potential. All the synthesized compounds exhibited significant anti-AChE and anti-BChE activity, with IC50 values in the range of 0.24-10.19 µM and 0.64-30.08 µM, respectively, using donepezil hydrochloride as the standard. Out of 19 compounds screened, 3 compounds, viz. 22, 40, and 43, caused 50% inhibition of AChE at 0.24, 0.25, and 0.25 µM, respectively. A kinetic study revealed them to be mixed-type inhibitors, binding with both the CAS and PAS sites of AChE. The above-selected compounds were found to be effective inhibitors of AChE-induced and self-mediated Aß1-42 aggregation. ADMET predictions demonstrated that these compounds may possess suitable blood-brain barrier (BBB) permeability. Hemolytic assay results revealed that these compounds did not lyse human RBCs up to a thousand times of their IC50 value. MTT assays performed for the shortlisted compounds showed them to be negligibly toxic after 24 h of treatment with the SH-SY5Y neuroblastoma cells. These results provide insights for further optimization of the scaffolds for designing the next generation of compounds as lead cholinesterase inhibitors.

Cross-sectional Pilot Study of Antibiotic Resistance in Propionibacterium Acnes Strains in Indian Acne Patients Using 16S-RNA Polymerase Chain Reaction: A Comparison Among Treatment Modalities Including Antibiotics, Benzoyl Peroxide, and Isotretinoin.

BACKGROUND: Antibiotic resistance is a worldwide problem in acne patients due to regional prescription practices, patient compliance, and genomic variability in Propionibacterium acnes, though the effect of treatment on the resistance has not been comprehensively analyzed. AIMS: Our primary objective was to assess the level of antibiotic resistance in the Indian patients and to assess whether there was a difference in the resistance across common treatment groups. SUBJECTS AND METHODS: A cross-sectional, institutional based study was undertaken and three groups of patients were analyzed, treatment naïve, those on antibiotics and patients on benzoyl peroxide (BPO) and/isotretinoin. The follicular content was sampled and the culture was verified with 16S rRNA polymerase chain reaction, genomic sequencing, and pulsed-field gel electrophoresis. Minimum inhibitory concentration (MIC) assessment was done for erythromycin (ERY), azithromycin (AZI), clindamycin (CL), tetracycline (TET), doxycycline (DOX), minocycline (MINO), and levofloxacin (LEVO). The four groups of patients were compared for any difference in the resistant strains. RESULTS: Of the 52 P. acnes strains isolated (80 patients), high resistance was observed to AZI (100%), ERY (98%), CL (90.4%), DOX (44.2%), and TETs (30.8%). Low resistance was observed to MINO (1.9%) and LEVO (9.6%). Statistical difference was seen in the resistance between CL and TETs; DOX/LEVO and DOX/MINO (P < 0.001). High MIC90 (≥256 µg/ml) was seen with CL, macrolides, and TETs; moreover, low MIC90 was observed to DOX (16 µg/ml), MINO (8 µg/ml), and LEVO (4 µg/ml). Though the treatment group with isotretinoin/BPO had the least number of resistant strains there was no statistical difference in the antibiotic resistance among the various groups of patients. CONCLUSIONS: High resistance was seen among the P. acnes strains to macrolides-lincosamides (AZI and CL) while MINO and LEVO resistance was low.