Actinobacteria as Microbial Cell Factories and Biocatalysts in The Synthesis of Chiral Intermediates and Bioactive Molecules; Insights and Applications.

Actinobacteria are one of the most intriguing bacterial phyla in terms of chemical diversity and bioactivities of their reported biomolecules and natural products, including various types of chiral molecules. Actinobacterial genera such as Detzia, Mycobacterium, and Streptomyces are among the microbial sources targeted for selective reactions such as asymmetric biocatalysis catalyzed by whole cells or enzymes induced in their cell niche. Remarkably, stereoselective reactions catalyzed by actinobacterial whole cells or their enzymes include stereoselective oxidation, stereoselective reduction, kinetic resolution, asymmetric hydrolysis, and selective transamination, among others. Species of actinobacteria function with high chemo-, regio-, and enantio-selectivity under benign conditions, which could help current industrial processing. Numerous selective enzymes were either isolated from actinobacteria or expressed from actinobacteria in other microbes and hence exploited in the production of pure organic compounds difficult to obtain chemically. In addition, different species of actinobacteria, especially Streptomyces species, function as natural producers of chiral molecules of therapeutic importance. Herein, we discuss some of the most outstanding contributions of actinobacteria to asymmetric biocatalysis, which are important in the organic and/or pharmaceutical industries. In addition, we highlight the role of actinobacteria as microbial cell factories for chiral natural products with insights into their various biological potentialities.

Novel N-methylsulfonyl-indole derivatives: biological activity and COX-2/5-LOX inhibitory effect with improved gastro protective profile and reduced cardio vascular risks.

Three novel series of N-methylsulfonylindole derivatives 3a&b, 4a-e, and 5a-e were synthesised. Different biological activities of the synthesised compounds were studied. Antimicrobial activity showed that, compounds 4b, 4e and 5d had selective antibacterial activity against the Gram-negative bacteria, Salmonella enterica and/or E. coli. The anti-oxidant activity of the synthesised compounds was evaluated by DPPH radical scavenging activity. In vitro anti-inflammatory activity was estimated. Compounds 4d, 4e, 5b, and 5d showed the highest anti-inflammatory activity. The COX-1, COX-2 and 5-LOX inhibitory activities were measured using enzyme immune assay (EIA) kits. Due to the dual COX-2/5-LOX inhibitory activity of compound 5d, its cardiovascular profile was determined by measuring cardiac biomarkers (LDH, CK-MB, and Tn-I). Besides, the histopathological study of the heart muscle and stomach were examined for the most active COX-2 inhibitors 4e and 5d. Finally, a molecular modelling study and pharmacokinetic properties were obtained using different computational methods.

Emergence of High Antimicrobial Resistance among Critically Ill Patients with Hospital-Acquired Infections in a Tertiary Care Hospital.

Background and Objectives: Inappropriate antibiotic usage in hospitalized patients contributes to microbial resistance. Our study aimed to examine the incidence of clinical bacterial isolates and their antibiotic resistance burden among critically ill patients in different hospital units. Materials and Methods: A single-centered cross-sectional study was conducted in a 120-bed tertiary care hospital that included 221 critically ill patients with hospital-acquired infections. Bacterial cultures and sensitivity reports were obtained and followed by a formal analysis of the antibiogram results to explore recovered isolates' prevalence and antibiotic susceptibility patterns. Results: Gram-negative bacteria were the most predominant pathogens among recovered isolates from the various hospital units (71%). Klebsiella sp. was the most prevalent microbe, followed by Acinetobacter sp., with an incidence level of 28% and 16.2%, respectively. Among the Gram-positive organisms, the coagulase-negative Staphylococci were the most predominant organism (11.3%), while (6.3%) methicillin-resistant Staphylococcus aureus (MRSA) isolates were recovered from different hospital units. Antibiotic sensitivity testing showed that polymyxin B was the most effective antibiotic against Gram-negative bacteria, whereas vancomycin and linezolid were the most active antibiotics against Gram-positive pathogens. Moreover, 7% of the Gram-negative bacteria isolated from different units showed positive production of extended-spectrum beta-lactamase (ESBL). Conclusions: The current study describes the high antibiotic resistance patterns in various hospital units that need extra legislation to prevent healthcare providers from misprescription and overuse of antibiotics.

Investigating the hepatoprotective potentiality of marine-derived steroids as promising inhibitors of liver fibrosis.

It has been reported that organic extracts derived from soft corals belonging to the genus Sarcophyton have exhibited a wide range of therapeutic characteristics. Based on biochemical and histological techniques, we aimed to assess the hepatoprotective role of the organic extract and its principal steroidal contents derived from the Red Sea soft coral Sarcophyton glaucum on acetaminophen-induced liver fibrosis in rats. Serum liver function parameters (ALT, AST, ALP and total bilirubin) were quantified using a spectrophotometer, and both alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA) levels were determined by using enzyme-linked immunosorbent assay (ELISA) kits while transformed growth factor beta (TGF-ß) and tumor necrosis factor α (TNF-α) in liver tissue homogenate were determined using ELISA, and TGF-ß and TNF-α gene expression in liver tissue was determined using real-time PCR following extraction and purification. Histopathological alterations in hepatic tissue were also examined under a microscope. In order to prioritize the isolation and characterization of the most promising marine steroids from the organic extract of the Red Sea soft coral Sarcophyton glaucum as hepatoprotective agents, a computational approach was employed. This approach involved molecular docking (MDock) and analysis of the structure-activity relationship (SAR) against glutathione-S-transferase (GST) and Cu-Zn human superoxide dismutase (Cu-ZnSOD) enzymes. Although the major role in the detoxification of foreign chemicals and toxic metabolites of GST and SOD enzymes is known, there is a lack of knowledge about the mode of action of the hepatoprotective process and those of the targets involved. The present study investigated the multiple interactions of a series of marine steroids with the GST and SOD enzymes, in order to reveal insights into the process of hepatoprotection.

Anti-cancer and antimicrobial potential of five soil Streptomycetes: a metabolomics-based study.

Lack of new anti-cancer and anti-infective agents directed the pharmaceutical research to natural products' discovery especially from actinomycetes as one of the major sources of bioactive compounds. Metabolomics- and dereplication-guided approach has been used successfully in chemical profiling of bioactive actinomycetes. We aimed to study the metabolomic profile of five bioactive actinomycetes to investigate the interesting metabolites responsible for their antimicrobial and anti-cancer activities. Three actinomycetes, namely, Streptomyces sp. SH8, SH10 and SH13, were found to exhibit broad spectrum of antimicrobial activities, whereas isolate SH4 showed the broadest antimicrobial activity against all tested strains. In addition, isolates SH8, SH10 and SH12 displayed potent cytotoxicity against the breast cancer cell line Michigan Cancer Foundation-7 (MCF-7), whereas isolates SH4 and SH12 exhibited potent anti-cancer activity against the hepatoma cell line hepatoma G2 (HepG2) compared with their weak inhibitory properties on the normal breast cells MCF-10A and normal liver cells transformed human liver epithelial-2 (THLE2), respectively. All bioactive isolates were molecularly identified as Streptomyces sp. via 16S rRNA gene sequencing. Our actinobacterial dereplication analysis revealed putative identification of several bioactive metabolites including tetracycline, oxytetracycline and a macrolide antibiotic, novamethymycin. Together, chemical profiling of bioactive Streptomycetes via dereplication and metabolomics helped in assigning their unique metabolites and predicting the bioactive compounds instigating their diverse bioactivities.

Chemical diversity, medicinal potentialities, biosynthesis, and pharmacokinetics of anthraquinones and their congeners derived from marine fungi: a comprehensive update.

Marine fungi receive excessive attention as prolific producers of structurally unique secondary metabolites, offering promising potential as substitutes or conjugates for current therapeutics, whereas existing research has only scratched the surface in terms of secondary metabolite diversity and potential industrial applications as only a small share of bioactive natural products have been identified from marine-derived fungi thus far. Anthraquinones derived from filamentous fungi are a distinct large group of polyketides containing compounds which feature a common 9,10-dioxoanthracene core, while their derivatives are generated through enzymatic reactions such as methylation, oxidation, or dimerization to produce a large variety of anthraquinone derivatives. A considerable number of reported anthraquinones and their derivatives have shown significant biological activities as well as highly economical, commercial, and biomedical potentialities such as anticancer, antimicrobial, antioxidant, and anti-inflammatory activities. Accordingly, and in this context, this review comprehensively covers the state-of-art over 20 years of about 208 structurally diverse anthraquinones and their derivatives isolated from different species of marine-derived fungal genera along with their reported bioactivity wherever applicable. Also, in this manuscript, we will present in brief recent insights centred on their experimentally proved biosynthetic routes. Moreover, all reported compounds were extensively investigated for their in-silico drug-likeness and pharmacokinetics properties which intriguingly highlighted a list of 20 anthraquinone-containing compounds that could be considered as potential drug lead scaffolds.

Correction: Bioassay- and metabolomics-guided screening of bioactive soil actinomycetes from the ancient city of Ihnasia, Egypt.

[This corrects the article DOI: 10.1371/journal.pone.0226959.].

Bioassay- and metabolomics-guided screening of bioactive soil actinomycetes from the ancient city of Ihnasia, Egypt.

Literature surveys, taxonomical differences, and bioassay results have been utilized in the discovery of new natural products to aid in Actinomycetes isolate-selection. However, no or less investigation have been done on establishing the differences in metabolomic profiles of the isolated microorganisms. The study aims to utilise bioassay- and metabolomics-guided tools that included dereplication study and multivariate analysis of the NMR and mass spectral data of microbial extracts to assist the selection of isolates for scaling-up the production of antimicrobial natural products. A total of 58 actinomycetes were isolated from different soil samples collected from Ihnasia City, Egypt and screened for their antimicrobial activities against indicator strains that included Bacillus subtilis, Escherichia coli, methicillin-resistant Staphylococcus aureus and Candida albicans. A number of 25 isolates were found to be active against B. subtilis and/or to at least one of the tested indicator strains. Principal component analyses showed chemical uniqueness for four outlying bioactive actinomycetes extracts. In addition, Orthogonal Projections to Latent Structures Discriminant Analysis (OPLS-DA) and dereplication study led us to further select two outlying anti-MRSA active isolates MS.REE.13 and 22 for scale-up work. MS.REE.13 and 22 exhibited zones of inhibition at 19 and 13 mm against MRSA, respectively. A metabolomics-guided approach provided the steer to target the bioactive metabolites (P<0.01) present in a crude extract or fraction even at nanogram levels but it was a challenge that such low-yielding bioactive natural products would be feasible to isolate. Validated to occur only on the active side of OPLS-DA loadings plot, the isolated compounds exhibited medium to weak antibiotic activity with MIC values between 250 and 800 µM. Two new compounds, P_24306 (C10H13N2) and N_12799 (C18H32O3) with MICs of 795 and 432 µM, were afforded from the scale-up of MS.REE. 13 and 22, respectively.