Culture filtrate of 2 actinomycetes extracted from marine sponge Crella cyathophora was used for the biosynthesis of AgNPs with a significant anti-microbial and biofilm activity. Also, AgNPs exhibited a low to moderate cytotoxicity against cells.

Recently, the interest in plant-derived antimicrobial agents has increased. However, there are no sufficient studies dealing with their modes of action. Herein, we investigate an in-house library of common plant-based phenolic compounds for their potential antibacterial effects against the methicillin-resistant Staphylococcus aureus (MRSA), a widespread life-threatening superbug. Flavonoids, which are considered major constituents in the plant kingdom, were found to be a promising class of compounds against MRSA, particularly the non-glycosylated ones. On the other hand, the glycosylated derivatives, along with the flavonolignan silibinin A, were able to restore the inhibitory activity of ampicillin against MRSA. To explore the mode of action of this class, they were subjected to an extensive inverse virtual screening (IVS), which suggested penicillin-binding protein 2a (PBP2a) as a possible target that mediates both the antibacterial and the antibiotic-synergistic effects of this class of compounds. Further molecular docking and molecular dynamic simulation experiments were conducted to support the primary IVS and the in vitro results and to study their binding modes with PBP2a. Our findings shed a light on plant-derived natural products, notably flavonoids, as a promising and readily available source for future adjuvant antimicrobial therapy against resistant strains.

Liquid chromatography coupled with high resolution mass spectrometry (LC-HRESMS)-assisted metabolomic profiling of two sponge-associated actinomycetes, Micromonospora sp. UR56 and Actinokineospora sp. EG49, revealed that the co-culture of these two actinomycetes induced the accumulation of metabolites that were not traced in their axenic cultures. Dereplication suggested that phenazine-derived compounds were the main induced metabolites. Hence, following large-scale co-fermentation, the major induced metabolites were isolated and structurally characterized as the already known dimethyl phenazine-1,6-dicarboxylate (1), phenazine-1,6-dicarboxylic acid mono methyl ester (phencomycin; 2), phenazine-1-carboxylic acid (tubermycin; 3), N-(2-hydroxyphenyl)-acetamide (9), and p-anisamide (10). Subsequently, the antibacterial, antibiofilm, and cytotoxic properties of these metabolites (1–3, 9, and 10) were determined in vitro. All the tested compounds except 9 showed high to moderate antibacterial and antibiofilm activities, whereas their cytotoxic effects were modest. Testing against Staphylococcus DNA gyrase-B and pyruvate kinase as possible molecular targets together with binding mode studies showed that compounds 1–3 could exert their bacterial inhibitory activities through the inhibition of both enzymes. Moreover, their structural differences, particularly the substitution at C-1 and C-6, played a crucial role in the determination of their inhibitory spectra and potency. In conclusion, the present study highlighted that microbial co-cultivation is an efficient tool for the discovery of new antimicrobial candidates and indicated phenazines as potential lead compounds for further development as antibiotic scaffold.

ContextDevelopment of optimal medicinal treatments of uterine leiomyomas represents a significant challenge. 2-Methoxyestradiol (2ME) is an endogenous estrogen metabolite formed by sequential action of CYP450s and catechol-O-methyltransferase (COMT). Our previous study demonstrated that 2ME is a potent antiproliferative, proapoptotic, antiangiogenic, and collagen synthesis inhibitor in human leiomyomas cells (huLM).ObjectivesOur objectives were to investigate whether COMT expression, by the virtue of 2ME formation, affects the growth of huLM, and to explore the cellular and molecular mechanisms whereby COMT expression or treatment with 2ME affect these cells.ResultsOur data demonstrated that E2-induced proliferation was less pronounced in cells over-expressing COMT or treated with 2ME (500 nM). This effect on cell proliferation was associated with microtubules stabilization and diminution of estrogen receptor α (ERα) and progesterone receptor (PR) transcriptional activities, due to shifts in their subcellular localization and sequestration in the cytoplasm. In addition, COMT over expression or treatment with 2ME reduced the expression of hypoxia-inducible factor -1α (HIF-1 α) and the basal level as well as TNF-α-induced aromatase (CYP19) expression.ConclusionsCOMT over expression or treatment with 2ME stabilize microtubules, ameliorates E2-induced proliferation, inhibits ERα and PR signaling, and reduces HIF-1 α and CYP19 expression in human uterine leiomyoma cells. Thus, microtubules are a candidate target for treatment of uterine leiomyomas. In addition, the naturally occurring microtubule-targeting agent 2ME represents a potential new therapeutic for uterine leiomyomas.

Marine endophytic fungi from under-explored locations are a promising source for the discovery of new bioactivities. Different endophytic fungi were isolated from plants and marine organisms collected from Wadi El-Natrun saline lakes and the Red Sea near Hurghada, Egypt. The isolated strains were grown on three different media, and their ethyl acetate crude extracts were evaluated for their antimicrobial activity against a panel of pathogenic bacteria and fungi as well as their antioxidant properties. Results showed that most of the 32 fungal isolates initially obtained possessed antimicrobial and antioxidant activities. The most potent antimicrobial extracts were applied to three different cellulose containing fabrics to add new multifunctional properties such as ultraviolet protection and antimicrobial functionality. For textile safety, the toxicity profile of the selected fungal extract was evaluated on human fibroblasts. The 21 strains displaying bioactivity were identified on molecular basis and selected for chemical screening and dereplication, which was carried out by analysis of the MS/MS data using the Global Natural Products Social Molecular Networking (GNPS) platform. The obtained molecular network revealed molecular families of compounds commonly produced by fungal strains, and in combination with manual dereplication, further previously reported metabolites were identified as well as potentially new derivatives.