Stress-induced biosynthesis of Streptazolin, Streptazone E/F, and clavulanic acid by <i>Streptomyces clavuligerus</i> KARE_KK2 under plastic-enriched high-salinity fermentation

Finding new bioactive metabolites offers a powerful solution to combat antibiotic resistance. Under plastic-enriched high salinity fermentation environment, Streptazolin, Streptazone E/F, and clavulanic acid biosynthesis by Streptomyces clavuligerus KARE_KK2, an actinobacterial isolate from termite mound soil, was studied. The fermentation medium was modified with 12% NaCl, 2% UV pretreated polythene, 2% plastic powder and 0.5% urea to mimic osmotic and xenobiotic stress. Post-10-day incubation with aeration, ethyl acetate was used to extract and analyze extracellular metabolites by LC-MS/MS. Streptazolin (a nitrogenous azoline), Streptazone E/F (azabicyclic electrophilic compounds), and Clavulanic acid (a clinically important β-lactamase inhibitor) are found in the metabolic profile. Because of chemical and environmental stress signals activation of silent or cryptic biosynthetic gene clusters on the part of these compounds are induced. Urea provided nitrogen, while the other factors likely act as small-molecule signaling in secondary metabolites regulation. This research shows that humans can help unlock the potential of actinobacteria, which are important to the pharmaceutical industry. Based on in silico molecular docking studies of Streptazolin and Clavulanic acid, it was observed that these two drug molecules could interact with <i>Staphylococcus aureus</i> exfoliative toxins A and B (ETA and ETB) which are the causative agents for Staphylococcal Scalded Skin Syndrome (SSSS). Further, it was also seen that Streptazolin and Clavulanic acid possessed the ability to bind with the human epidermal desmoglein-1, and hence have tremendous potential to act as SSSS toxin inhibitors. The results suggest the pharmaceutical potential of these metabolites, as well as a new way to use plastic waste as a microbial inducer for antibiotic discovery in biotechnology.