Isolation, characterization, anti-MRSA evaluation, and in-silico multi-target anti-microbial validations of actinomycin X2 and actinomycin D produced by novel Streptomyces smyrnaeus UKAQ_23.

Streptomyces smyrnaeus UKAQ_23, isolated from the mangrove-sediment, collected from Jubail,Saudi Arabia, exhibited substantial antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA), including non-MRSA Gram-positive test bacteria. The novel isolate, under laboratory-scale conditions, produced the highest yield (561.3 ± 0.3 mg/kg fermented agar) of antimicrobial compounds in modified ISP-4 agar at pH 6.5, temperature 35 °C, inoculum 5% v/w, agar 1.5% w/v, and an incubation period of 7 days. The two major compounds, K1 and K2, were isolated from fermented medium and identified as Actinomycin X2 and Actinomycin D, respectively, based on their structural analysis. The antimicrobial screening showed that Actinomycin X2 had the highest antimicrobial activity compared to Actinomycin D, and the actinomycins-mixture (X2:D, 1:1, w/w) against MRSA and non-MRSA Gram-positive test bacteria, at 5 µg/disc concentrations. The MIC of Actinomycin X2 ranged from 1.56-12.5 µg/ml for non-MRSA and 3.125-12.5 µg/ml for MRSA test bacteria. An in-silico molecular docking demonstrated isoleucyl tRNA synthetase as the most-favored antimicrobial protein target for both actinomycins, X2 and D, while the penicillin-binding protein-1a, was the least-favorable target-protein. In conclusion, Streptomyces smyrnaeus UKAQ_23 emerged as a promising source of Actinomycin X2 with the potential to be scaled up for industrial production, which could benefit the pharmaceutical industry.

Cross-Interplay between Osmolytes and mTOR in Alzheimer's Disease Pathogenesis.

Alzheimer's disease, categorized by the piling of amyloid-ß (Aß), hyperphosphorylated tau, PHFs, NFTs and mTOR hyperactivity, is a neurodegenerative disorder, affecting people across the globe. Osmolytes are known for osmoprotectants and play a pivotal role in protein folding, function and protein stability, thus, preventing proteins aggregation, and counteracting effects of denaturing solutes on proteins. Osmolytes (viz., sorbitol, inositol, and betaine) perform a pivotal function of maintaining homeostasis during hyperosmotic stress. The selective advantage of utilising osmolytes over inorganic ions by cells is in maintaining cell volume without compromising cell function, which is important for organs such as the brain. Osmolytes have been documented not only as neuroprotectors but they also seem to act as neurodegenerators. Betaine, sucrose and trehalose supplementation has been seen to induce autophagy thereby inhibiting the accumulation of Aß. In contrast, sucrose has also been associated with mTOR hyperactivity, a hallmark of AD pathology. The neuroprotective action of taurine is revealed when taurine supplementation is seen to inhibit neural damage, apoptosis and oxidative damage. Inositol stereoisomers (viz., scyllo-inositol and myo-inositol) have also been seen to inhibit Aß production and plaque formation in the brain, inhibiting AD pathogenesis. However, TMAO affects the aging process adversely by deregulating the mTOR signalling pathway and then kindling cognitive dysfunction via degradation of chemical synapses and synaptic plasticity. Thus, it can be concluded that osmolytes may act as a probable therapeutic approach for neurodevelopmental disorders. Here, we have reviewed and focussed upon the impact of osmolytes on mTOR signalling pathway and thereby its role in AD pathogenesis.