Manipulation and epigenetic control of silent biosynthetic pathways in actinobacteria.

Most biosynthetic gene clusters (BGCs) of Actinobacteria are either silent or expressed less than the detectable level. The non-genetic approaches including biological interactions, chemical agents, and physical stresses that can be used to awaken silenced pathways are compared in this paper. These non-genetic induction strategies often need screening approaches, including one strain many compounds (OSMAC), reporter-guided mutant selection, and high throughput elicitor screening (HiTES) have been developed. Different types of genetic manipulations applied in the induction of cryptic BGCs of Actinobacteria can be categorized as genome-wide pleiotropic and targeted approaches like manipulation of global regulatory systems, modulation of regulatory genes, ribosome and engineering of RNA polymerase or phosphopantheteine transferases. Targeted approaches including genome editing by CRISPR, mutation in transcription factors and modification of BGCs promoters, inactivation of the highly expressed biosynthetic pathways, deleting the suppressors or awakening the activators, heterologous expression, or refactoring of gene clusters can be applied for activation of pathways which are predicted to synthesize new bioactive structures in genome mining studies of Acinobacteria. In this review, the challenges and advantages of employing these approaches in induction of Actinobacteria BGCs are discussed. Further, novel natural products needed as drug for pharmaceutical industry or as biofertilizers in agricultural industry can be discovered even from known species of Actinobactera by the innovative approaches of metabolite biosynthesis elicitation.

Modulation of proteins by rare earth elements as a biotechnological tool.

Although rare earth element (REE) complexes are often utilized in bioimaging due to their photo- and redox stability, magnetic and optical characteristics, they are also applied for pharmaceutical applications due to their interaction with macromolecules namely proteins. The possible implications induced by REEs through modification in the function or regulatory activity of the proteins trigger a variety of applications for these elements in biomedicine and biotechnology. Lanthanide complexes have particularly been applied as anti-biofilm agents, cancer inhibitors, potential inflammation inhibitors, metabolic elicitors, and helper agents in the cultivation of unculturable strains, drug delivery, tissue engineering, photodynamic, and radiation therapy. This paper overviews emerging applications of REEs in biotechnology, especially in biomedical imaging, tumor diagnosis, and treatment along with their potential toxic effects. Although significant advances in applying REEs have been made, there is a lack of comprehensive studies to identify the potential of all REEs in biotechnology since only four elements, Eu, Ce, Gd, and La, among 17 REEs have been mostly investigated. However, in depth research on ecotoxicology, environmental behavior, and biological functions of REEs in the health and disease status of living organisms is required to fill the vital gaps in our understanding of REEs applications.

Mining the soil myxobacteria and finding sources of anti-diabetic metabolites.

Secondary metabolites produced by myxobacterial genera are often characterized as diverse molecules with unique structural properties which drove us to search for myxobacterial source of anti-diabetic drug discovery. In the present study, from 80 soil samples, out of sixty-five observed isolates, 30 and 16 were purified as Myxococcus and non-Myxococcus, respectively. Isolated strains taxonomically belonged to the genera Myxococcus, Corallococcus and Cystobacter, Archangium, Nanocystis, and Sorangium, and some could not be attributed. Secondary metabolites of selected non-Myxococcus isolates extracted by the liquid-liquid method showed that the myxobacterium UTMC 4530 demonstrated the highest inhibition on the formation of carbonyl group and fructosamine, respectively. In addition, it showed 23% and 15.8% inhibitory activity on α-glucosides and α-amylase compared to acarbose (23%, 18%), respectively. The extract of strain UTMC 4530 showed 35% induction effect on glucose adsorption while showing no radical scavenging activity and no toxic effect on HRBC lysis and HepG2 in cytotoxicity assays. The strain UTMC 4530 (ON808962), with the multiple antidiabetic activity, showed 87.3% similarity to Corallococcus llansteffanensis which indicates its affiliation to a new genus. The results of this study revealed that secondary metabolites produced by strain UTMC 4530 can be considered a promising source to find new therapeutic and pharmaceutical applications perhaps a multi-mechanism anti-diabetic compound.

Augmented antiviral activity of chlorhexidine gluconate on herpes simplex virus type 1, H1N1 influenza A virus, and adenovirus in combination with salicylic acid.

BACKGROUND: The excessive usage of chlorhexidine gluconate (CHG) as a broad-spectrum antimicrobial reagent can have a negative impact on the environment and on human health. The aim of this study was to investigate the effectiveness of some plant-derived compounds in reducing the CHG concentration required to exert its antiviral activity. METHODS: Antiviral assays were conducted according to EN 14476 (2019) against herpes simplex virus type 1 (HSV-1), H1N1 influenza A virus, and adenovirus type 5 (Ad-5) as enveloped and non-enveloped viral models to assess the synergistic interaction of CHG and natural additive compounds. RESULTS: The effective concentration of 0.247 mM CHG against HSV-1 was decreased tenfold in combination with 0.0125 mM salicylic acid, with a titer reduction of 1.47 ⋅ 104 CCID50/ml. The time required for complete inactivation of HSV-1 particles was reduced to 15 min when the virus was exposed to 0.061 mM CHG and 0.0125 mM salicylic acid. Additionally, the presence of salicylic acid protected the CHG activity against interfering substances. CONCLUSION: Our supplemented CHG formulation showed immediate antiviral effectiveness, which is important for management of the infections. CHG can be combined with salicylic acid to exhibit synergistic antiviral activity at lower concentrations and reduce the time required for inactivation. Furthermore, in the presence of interfering substances, the combination has higher antiviral activity than CHG alone.

Neurological manifestations of SARS-CoV-2 infections: towards quantum dots based management approaches.

Developing numerous nanotechnological designed tools to monitor the existence of SARS-CoV-2, and modifying its interactions address the global needs for efficient remedies required for the management of COVID-19. Herein, through a multidisciplinary outlook encompassing different fields such as the pathophysiology of SARS-CoV-2, analysis of symptoms, and statistics of neurological complications caused by SARS-CoV-2 infection in the central and peripheral nervous systems have been testified. The anosmia (51.1%) and ageusia (45.5%) are reported the most frequent neurological manifestation. Cerebrovascular disease and encephalopathy were mainly related to severe clinical cases. In addition, we focus especially on the various concerned physiological routes, including BBB dysfunction, which transpired due to SARS-CoV-2 infection, direct and indirect effects of the virus on the brain, and also, the plausible mechanisms of viral entry to the nerve system. We also outline the characterisation, and the ongoing pharmaceutical applications of quantum dots as smart nanocarriers crossing the blood-brain barrier and their importance in neurological diseases, mainly SARS-CoV-2 related manifestations Moreover, the market status, six clinical trials recruiting quantum dots, and the challenges limiting the clinical application of QDs are highlighted.

Suppression of predominant interfering bacteria in the purification process of myxobacteria.

Background and Objectives: Myxobacteria initially recognized by their complex life cycle and social behavior are progressively explored for their bioactive secondary metabolites. However, isolation of myxobacteria usually is accompanied by bacterial and fungal contaminations due to the direct cultivation of soil on isolation media, which results in severe challenges in the purification of myxobacteria. Therefore, it is necessary to improve their purification techniques from natural samples to the discovery of new biomolecules. Materials and Methods: In the present study, six physichochemical methods were assessed for their efficacy in the purification of myxobacterial strains and specially from contaminants of Microvirga spp. Results: Among the evaluated treatments, purification of fruiting bodies using a combination of ultrasonication and heat treatment was identified as the effective protocol with 80% success rate in the purification of myxobacterial strains and reducing up to 90% of the contaminating bacteria. Conclusion: Concerning the problematic contamination of myxobacterial isolates, the introduced approach can retrieve the myxobacterial strains which are often suppressed by the over growth of contaminations especially root symbiotic bacteria namely Microvirga spp.

Neurological disorders of COVID-19: insights to applications of natural products from plants and microorganisms.

In addition to the typical respiratory manifestations, various disorders including involvement of the nerve system have been detected in COVID-19 ranging from 22 to 36%. Although growing records are focusing on neurological aspects of COVID-19, the pathophysiological mechanisms and related therapeutic methods remain obscure. Considering the increased concerns of SARS-CoV-2 potential for more serious neuroinvasion conditions, the present review attempts to focus on the neuroprotective effects of natural compounds as the principle source of therapeutics inhibiting multiple steps of the SARS-CoV-2 infection cycle. The great majority of the natural products with anti-SARS-CoV-2 activity mainly inhibit the attachment, entry and gene expression rather than the replication, assembly, or release. Although microbial-derived natural products comprise 38.5% of the known natural products with neuroprotective effects following viral infection, the neuroprotective potential of the majority of microorganisms is still undiscovered. Among natural products, chrysin, huperzine A, ginsenoside Rg1, pterostilbene, and terrein have shown potent in vitro neuroprotective activity and can be promising for new or repurpose drugs for neurological complications of SARS-CoV-2.

Nanomaterial-Augmented Formulation of Disinfectants and Antiseptics in Controlling SARS CoV-2.

The worldwide COVID-19 pandemic has brought significant consideration toward innovative strategies for overcoming the viral spread. Nanotechnology will change our lives in several forms as its uses span from electronics to pharmaceutical procedures. The use of nanoparticles provides a possibility to promote new antiviral treatments with a low possibility of increasing drug resistance compared to typical chemical-based antiviral treatments. Since the long-term usage of disinfectants and antiseptics at high concentrations has deleterious impacts on well-being and the environment, this review was intended to discuss the antiviral activity of disinfectants and antiseptics required for their activity against respiratory viruses especially SARS-CoV-2. It could improve the inhibition of viral penetration into cells, solvation of the lipid bilayer envelope, and ROS production, therefore enhancing the effect of disinfectants. However, significant concerns about nanomaterial's hazardous effects on individuals and the environment are increasing as nanotechnology flourishes. In this review, we first discuss the significant and essential types of nanomaterials, especially silver and copper, that could be used as antiviral agents and their viral entry mechanisms into host cells. Further, we consider the toxicity on health, and environmental concerns of nanoparticles. Eventually, we present our outlook on the fate of nanomaterials toward viral diseases.

In vitro and in silico pharmaceutical activities of the methylated cyclic pentapeptide, persipeptides.

AIMS: The persipeptides were recognized as a promising source of multiple pharmaceutical activities which were revealed following structure-activity prediction and examination in experimental analysis. METHODS AND RESULTS: The profile of toxicity, antioxidant, anti-inflammatory, anti-diabetic and anti-ageing activity of persipeptides and the crude extract were evaluated experimentally. The pure Persipeptide A and B revealed a moderate xanthine oxidase inhibition activity at the concentration of 10 µg/ml. Persipeptide exhibited α-glucosidase inhibition activity (~10% inhibition) and less than 2% tyrosinase inhibition activity at the concentration of 10 µg/ml. The extract exhibited the inhibition of less than 2% acetylcholine esterase inhibition activity, but the pure persipeptide showed 6%-14% inhibition activity at the concentration of 10 µg/ml. The molecular docking analysis revealed that the activities of Persipeptide A and B are due to interaction with xanthin oxidase, α-amylase, α-glucosidase, tyrosinase and acetylcholine esterase enzymes. CONCLUSIONS: The persipeptides showed a similar inhibition rate with positive control that might imply its potential as an anti-diabetic and anti-gout compound among. Only acetylcholine esterase inhibition of persipeptide was higher than the extract. The interacting amino acids of the molecules with different targets show that persipeptides might have antioxidant, anti-inflammatory, anti-diabetic, anti-ageing activity and even other potential pharmaceutical activities that were not investigated in this study. SIGNIFICANCE AND IMPACT OF THE STUDY: This report was presented to find some new pharmaceutical activities of Persipeptide A and B including the α-glucosidase inhibition activity as a molecular target of diabetes mellitus. Persipeptides also exhibited an effective inhibition of xanthine oxidase (XO) which can be a drug-like candidate in the treatment of diseases associated with XO like gout. The binding values indicated the interaction of persipeptides with these enzymes.

Enhancement of bactericidal effect of Chlorhexidine using choline augmentation as a natural additive.

BACKGROUND: The long-term use of Chlorhexidine (CHG) at high concentrations has detrimental effects on health and the environment. This research was aimed to evaluate the antibacterial capacity of CHG in the presence of choline as a natural additive to reduce the amount CHG required for the activity. METHODS: The newly obtained formulation was evaluated for its stability and efficiency under physicochemical stresses. The checkerboard test was also performed to evaluate the type of CHG-additive interaction in a combinational state. RESULTS: The MIC of CHG was reduced up to five-fold in combination with choline at the concentration of 50mg/L and five log cfu/mL at 3 minutes of exposure. Chlorhexidine activity in combination with choline was preserved 20% more in the presence of interfering substances. The activity between CHG and choline was demonstrated as synergistic with FICI of 0.375. At sub MIC concentrations of both CHG (≤20 mg/L) and choline (≤6 mg/L) the observed interaction was synergy. While the significant interaction at high concentrations for both compounds was indifferent manner. The lysis effect of the CHG 20 mg/L was diminished in the presence of choline. CONCLUSIONS: Our suggested CHG formulation demonstrated rapid antimicrobial efficacy which can be a useful adjunct to infection control strategies currently employed in healthcare facilities. In conclusion, CHG can be combined with natural compounds as additives for enhanced synergistic antimicrobial activity.

Fruit wrapping kraft coated paper promotes the isolation of actinobacteria using ex situ and in situ methods.

Designing novel isolation methods could enhance the diversification of the available bacterial strains to biotechnology. In this study, the new ex situ and in situ cultivation methods are introduced for the isolation of actinobacteria. In the ex situ experiments, the soil suspension was spread on the isolation media located above some ordinary papers in immediate contact with the slurry of soil substrate and incubated for 16 weeks. The paper was wholly immersed in the cave soil for in situ cultivations, and the containers were buried under layers of soil in Hampoeil cave for 10 weeks. Fruit wrapping kraft coated paper, with 68.8% recovery of isolates, was a better choice in isolation of actinobacteria than other studied filter paper. Based on the molecular identification results, 19% of the isolates obtained from the in situ cultivation method had less than 98.5% similarity to known taxa of actinobacteria and potentially may represent new species. In contrast, in the standard cultivation method, 1.3% of the isolates had less than 98.5% similarity 16Sr RNA gene. This data shows that the introduced cultivation method is a promising technique for isolating less culturable or new actinobacteria.

Biodiversity, phylogeny and toxin production profile of cyanobacterial strains isolated from lake Latyan in Iran.

Monitoring toxigenic cyanobacteria in freshwaters is of great importance due to the adverse health impacts on humans and aquatic organisms. Here we studied cyanobacterial occurrence and biodiversity in a drinking water reservoir in Tehran province, Iran. In total, nine different species representing three orders of Synechococcales, Oscillatoriales and Nostocales were isolated and classified into six families and seven genera ranging from 92.3% to 99.0% similarities in their partial 16S rDNA with GenBank sequences. The cultures were analyzed for cyanotoxins production by the Artemia salina bioassay, ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and also screened for the presence of marker genes involved in toxins production. Ethyl acetate extracts of three strains showed more than 50% mortality on A. salina larvae after 24 h at a concentration of 500 µg/ml. Production of at least one of the cyanotoxins, microcystin (MC), cylindrospermopsin (CYN) and anatoxin-a (ATX-a), was detected in 6 of the strains. Seven MC variants with a total concentration of 130.6 ng/mg of biomass dry weight were detected for the strain Phormidium sp. UTMC6001 and molecular screening of the mcyE gene also confirmed the presence of this biomarker in its genome. Our study also revealed the production of CYN in a novel picocyanobacterial strain Cyanobium sp. UTMC6007 at 1.0 ng/mg of biomass dry weight. Considering the limited information on freshwater toxic cyanobacteria taxonomy in the Middle East, these findings will expand our knowledge and consequently aid in development of new water management policies in future.

Contribution of machine learning approaches in response to SARS-CoV-2 infection.

PROBLEM: The lately emerged SARS-CoV-2 infection, which has put the whole world in an aberrant demanding situation, has generated an urgent need for developing effective responses through artificial intelligence (AI). AIM: This paper aims to overview the recent applications of machine learning techniques contributing to prevention, diagnosis, monitoring, and treatment of coronavirus disease (SARS-CoV-2). METHODS: A progressive investigation of the recent publications up to November 2020, related to AI approaches towards managing the challenges of COVID-19 infection was made. RESULTS: For patient diagnosis and screening, Convolutional Neural Network (CNN) and Support Vector Machine (SVM) are broadly applied for classification purposes. Moreover, Deep Neural Network (DNN) and homology modeling are the most used SARS-CoV-2 drug repurposing models. CONCLUSION: While the fields of diagnosis of the SARS-CoV-2 infection by medical image processing and its dissemination pattern through machine learning have been sufficiently studied, some areas such as treatment outcome in patients and drug development need to be further investigated using AI approaches.

Potential of blockchain approach on development and security of microbial databases.

Approaches developed based on the blockchain concept can provides a framework for the realization of open science. The traditional centralized way of data collection and curation is a labor-intensive work that is often not updated. The fundamental contribution of developing blockchain format of microbial databases includes: 1. Scavenging the sparse data from different strain database; 2. Tracing a specific thread of access for the purpose of evaluation or even the forensic; 3. Mapping the microbial species diversity; 4. Enrichment of the taxonomic database with the biotechnological applications of the strains and 5. Data sharing with the transparent way of precedent recognition. The plausible applications of constructing microbial databases using blockchain technology is proposed in this paper. Nevertheless, the current challenges and constraints in the development of microbial databases using the blockchain module are discussed in this paper.

Hypothetical targets and plausible drugs of coronavirus infection caused by SARS-CoV-2.

The world is confronting a dire situation due to the recent pandemic of the novel coronavirus disease (SARS-CoV-2) with the mortality rate passed over 470,000. Attaining efficient drugs evolve in parallel to the understanding of the SARS-CoV-2 pathogenesis. The current drugs in the pipeline and some plausible drugs are overviewed in this paper. Although different types of anti-viral targets are applicable for SARS-CoV-2 drug screenings, the more promising targets can be considered as 3C-like main protease (3Cl protease) and RNA polymerase. The remdesivir could be considered the closest bifunctional drug to the provisional clinical administration for SARS-CoV-2. The known molecular targets of the SARS-CoV-2 include fourteen targets, while four molecules of angiotensin-converting enzyme 2 (ACE2), cathepsin L, 3Cl protease and RNA-dependent RNA polymerase (RdRp) are suggested as more promising potential targets. Accordingly, dual-acting drugs as an encouraging solution in drug discovery are suggested. Emphasizing the potential route of SARS-CoV-2 infection and virus entry-related factors like integrins, cathepsin and ACE2 seems valuable. The potential molecular targets of each phase of the SARS-CoV-2 life cycle are discussed and highlighted in this paper. Much progress in understanding the SARS-CoV-2 and molecular details of its life cycle followed by the identification of new therapeutic targets are needed to lead us to an efficient approach in anti-SARS-CoV-2 drug discovery.

Prominent and emerging anti-diabetic molecular targets.

Diabetes is on the rise across the globe affecting more than 463 million people and crucially increasing morbidities of diabetes-associated diseases. Urgent and immense actions are needed to improve diabetes prevention and treatment. Regarding the correlation of diabetes with many associated diseases, inhibition of the disease progression is more crucial than controlling symptoms. Currently, anti-diabetic drugs are accompanied by undesirable side-effects and target confined types of biomolecules. Thus, extensive research is demanding to identify novel disease mechanisms and molecular targets as probable candidates for effective treatment of diabetes. This review discusses the conventional molecule targets that have been applied for their therapeutic rationale in treatment of diabetes. Further, the emerging and prospective molecular targets for the future focus of library screenings are presented.

Physicochemical susceptibility of SARS-CoV-2 to disinfection and physical approach of prophylaxis.

The transmission control of the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the most effective strategy by the absence of its specified vaccine or drug. Although the aerosol mediated transmission of SARS-CoV-2 has been confirmed, the physicochemical treatment of the biotic and abiotic objects is still the most promising approach in its infection control. The front line of the most effective disinfecting compounds on SARS-CoV-2 implies to be sodium hypochlorite, ethanol, hydrogen peroxide, quaternary ammonium compounds, and phenolic compounds, respectively. However, widely used compounds of alkyldimethylbenzylammonium chloride (benzalkonium chloride) biguanides (chlorhexidine) have not shown the multitude load reduction in less than 10 minutes. The susceptibility of SARS-CoV-2 to physical treatment follows the pattern of heat, acidity, and UV radiation. Rather all of the mentioned physical or chemical treatments, target the envelope proteins of the coronavirus mainly by impairing its entry to host cells. The anti-SARS-CoV-2 activity of combinatorial physicochemical treatments or evaluation of new chemical entities or physical treatments such as microwave irradiation still needs to be explored. Therefore, the development of a reliable decontamination protocol for SARS-CoV-2 demands revealing its stability pattern study vs a spectrum of single and combinatorial physicochemical parameters.

Spectrum of deep learning algorithms in drug discovery.

Deep learning (DL) algorithms are a subset of machine learning algorithms with the aim of modeling complex mapping between a set of elements and their classes. In parallel to the advance in revealing the molecular bases of diseases, a notable innovation has been undertaken to apply DL in data/libraries management, reaction optimizations, differentiating uncertainties, molecule constructions, creating metrics from qualitative results, and prediction of structures or interactions. From source identification to lead discovery and medicinal chemistry of the drug candidate, drug delivery, and modification, the challenges can be subjected to artificial intelligence algorithms to aid in the generation and interpretation of data. Discovery and design approach, both demand automation, large data management and data fusion by the advance in high-throughput mode. The application of DL can accelerate the exploration of drug mechanisms, finding novel indications for existing drugs (drug repositioning), drug development, and preclinical and clinical studies. The impact of DL in the workflow of drug discovery, design, and their complementary tools are highlighted in this review. Additionally, the type of DL algorithms used for this purpose, and their pros and cons along with the dominant directions of future research are presented.

Emerging biosensors in detection of natural products.

Natural products (NPs) are a valuable source in the food, pharmaceutical, agricultural, environmental, and many other industrial sectors. Their beneficial properties along with their potential toxicities make the detection, determination or quantification of NPs essential for their application. The advanced instrumental methods require time-consuming sample preparation and analysis. In contrast, biosensors allow rapid detection of NPs, especially in complex media, and are the preferred choice of detection when speed and high throughput are intended. Here, we review diverse biosensors reported for the detection of NPs. The emerging approaches for improving the efficiency of biosensors, such as microfluidics, nanotechnology, and magnetic beads, are also discussed. The simultaneous use of two detection techniques is suggested as a robust strategy for precise detection of a specific NP with structural complexity in complicated matrices. The parallel detection of a variety of NPs structures or biological activities in a mixture of extract in a single detection phase is among the anticipated future advancements in this field which can be achieved using multisystem biosensors applying multiple flow cells, sensing elements, and detection mechanisms on miniaturized folded chips.

Awakening the Secondary Metabolite Pathways of Promicromonospora kermanensis Using Physicochemical and Biological Elicitors.

The drug discovery rate is dramatically decreasing due to the rediscovery of known compounds. Genome mining approaches have revealed that a large portion of the actinobacterial genome that encodes bioactive metabolites is cryptic and not expressed under standard lab conditions. In the present study, we aimed to induce antibiotic encoding biosynthetic genes in a member of Micrococcales as a new species of Promicromonospora, Promicromonospora kermanensis, by chemical and biological elicitors as it was considered to produce numerous valuable bioactive metabolites based on the whole genome results. Induction has been done via chemical (antibiotics, histone deacetylase inhibitors (HDAIs), rare earth elements (REEs), fatty acid synthesis inhibitors, and extreme pH changes) and biological elicitors (live and dead Gram-positive and negative bacteria). The results showed that valproic acid (as HDAIs), DMSO, lanthanum chloride (as REE), triclosan (as fatty acid synthesis inhibitors), alkaline pH, and supernatant of Pseudomonas aeruginosa UTMC 1404 culture could act as stimuli to provoke antibacterial synthetic pathways in Promicromonospora kermanensis DSM 45485. Moreover, it was revealed that eliciting agents in cell filtrated of P. aeruginosa culture is resistant to detergent, acidic, and basic condition and have amphipathic nature. The inducing effect of alkaline pH on metabolite induction of Actinobacteria was first reported in this study. In the follow-up studies, the induced antibacterial producing clusters can be subjected to the characterization, and the implemented approach in this study can be used for metabolites induction in other selected species.