Potential drug candidates derived from natural sources are posed for the development of anti-SARS CoV-2 therapeutics.

Summary The prevalence of multidrug‐resistant microbial pathogens due to the continued misuse and overuse of antibiotics in agriculture and medicine is raising the prospect of a return to the preantibiotic days of medicine at the time of diminishing numbers of drug leads. The good news is that an increased understanding of the nature and extent of microbial diversity in natural habitats coupled with the application of new technologies in microbiology and chemistry is opening up new strategies in the search for new specialized products with therapeutic properties. This review explores the premise that harsh environmental conditions in extreme biomes, notably in deserts, permafrost soils and deep‐sea sediments select for micro‐organisms, especially actinobacteria, cyanobacteria and fungi, with the potential to synthesize new druggable molecules. There is evidence over the past decade that micro‐organisms adapted to life in extreme habitats are a rich source of new specialized metabolites. Extreme habitats by their very nature tend to be fragile hence there is a need to conserve those known to be hot‐spots of novel gifted micro‐organisms needed to drive drug discovery campaigns and innovative biotechnology. This review also provides an overview of microbial‐derived molecules and their biological activities focusing on the period from 2010 until 2018, over this time 186 novel structures were isolated from 129 representatives of microbial taxa recovered from extreme habitats.

The main protease (Mpro) of the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was subjected to hyphenated pharmacophoric-based and structural-based virtual screenings using a library of microbial natural products (>24,000 compounds). Subsequent filtering of the resulted hits according to the Lipinski’s rules was applied to select only the drug-like molecules. Top-scoring hits were further filtered out depending on their ability to show constant good binding affinities towards the molecular dynamic simulation (MDS)-derived enzyme’s conformers. Final MDS experiments were performed on the ligand–protein complexes (compounds 1–12, Table S1) to verify their binding modes and calculate their binding free energy. Consequently, a final selection of six compounds (1–6) was proposed to possess high potential as anti-SARS-CoV-2 drug candidates. Our study provides insight into the role of the Mpro structural flexibility during interactions with the possible inhibitors and sheds light on the structure-based design of anti-coronavirus disease 2019 (COVID-19) therapeutics targeting SARS-CoV-2.

Objective The repurposing of nitazoxanide, doxycycline and azithromycin may be effective to improve the symptoms in mild and moderate COVID‐19 subjects. This study aimed to detect and explain the efficacy of reusing of these drugs in treating COVID‐19. Methods The study was divided into two parts: clinical and computational parts. In the clinical part, 80 (30 females) subjects with reverse transcription‐polymerase chain reaction‐confirmed COVID‐19 with mild and moderate symptoms were enrolled in the study. Subjects were treated with azithromycin or doxycycline, and nitazoxanide was added to the treatment if the subject had diarrhoea. Subjects were divided into four groups: Group 1: subjects treated with azithromycin (20 subjects); Group 2: subjects treated with doxycycline (20 subjects); Group 3: subjects treated with a combination of nitazoxanide and doxycycline (20 subjects); and Group 4: subjects treated with a combination of nitazoxanide and azithromycin (20 subjects). In the computational part, we docked the three drugs against all currently available COVID‐19‐related protein targets (viral and non‐viral). Subsequently, top hits were subjected to molecular dynamic simulations (MDSs) (50 ns) and binding free energy calculations to further validate the docking experiments and to investigate the binding modes of the potential inhibitors. Results The symptomatic improvement of mild to moderate subjects was seen on the fifth day after starting treatment in Group 3 and Group 4 and on the seventh day in Group 2. However, for Group 1, the symptomatic improvement of mild to moderate subjects was not seen on the fifth day and required replacement by doxycycline to get the symptomatic improvement. None of the subjects needed intensive care admission and no deaths were reported. In silico, results were in good accordance with the clinical outcomes, where both nitazoxanide and doxycycline achieved the best docking scores against the viral ADP‐ribose phosphatase (ADPRP) and the human Adaptor‐Associated Kinase 1 (AAK1). MDSs revealed that both drugs were stable in their bindings indicating that they can be considered as lead molecules for targeting ADPRP and AAK1. Conclusion The clinical and computational studies applied on three FDA‐approved antimicrobials together with their recent clinical findings revealed that both nitazoxanide and doxycycline have great therapeutic potential against COVID‐19. The future in vitro mechanistic investigation may confirm our primary computational outcomes, and in turn, these classes of compounds provide a promising starting point for further anti‐COVID‐19 therapeutics.

In the present study, LC-HRESIMS-assisted dereplication along with bioactivity-guided isolation led to targeting two brominated oxindole alkaloids (compounds 1 and 2) which probably play a key role in the previously reported antibacterial, antibiofilm, and cytotoxicity of Callyspongia siphonella crude extracts. Both metabolites showed potent antibacterial activity against Gram-positive bacteria, Staphylococcus aureus (minimum inhibitory concentration (MIC) = 8 and 4 µg/mL) and Bacillus subtilis (MIC = 16 and 4 µg/mL), respectively. Furthermore, they displayed moderate biofilm inhibitory activity in Pseudomonas aeruginosa (49.32% and 41.76% inhibition, respectively), and moderate in vitro antitrypanosomal activity (13.47 and 10.27 µM, respectively). In addition, they revealed a strong cytotoxic effect toward different human cancer cell lines, supposedly through induction of necrosis. This study sheds light on the possible role of these metabolites (compounds 1 and 2) in keeping fouling organisms away from the sponge outer surface, and the possible applications of these defensive molecules in the development of new anti-infective agents.