Exploitation of actinomycetes from coastal ecosystems of İzmir Peninsula for antimicrobial activity via strain identification, untargeted metabolomics and drug combination studies

Antimicrobial resistance poses a major global health threat, highlighting the urgent need for novel bioactive compounds. Actinomycetes in the phylum Actinomycetota are prolific producers of antimicrobial agents; however, marine-derived strains remain underexplored, despite their ecological diversity and biosynthetic potential. In this study, we investigated the antimicrobial properties of Actinomycetes isolated from coastal sediments of İzmir Peninsula, situated on the Aegean Sea. Our extensive isolation efforts yielded 945 strains from 46 sediment samples. Overall, 38% of their extracts exhibited antibacterial or antifungal activity against at least one of the tested human pathogens. Based on prominent activities and chemical richness, fifteen potent extracts were selected for metabolomics, strain identification, and drug combination studies. MS²-based dereplication studies identified known antimicrobials, including chromomycin A3, leucomycin A1, actinomycin D, K-41 A, collismycin A, desferrioxamine E, terragine E, tirandamycin A, bafilomycin C1, and their derivatives, as well as chloramphenicol, lauramine-oxide, and staurosporine. Molecular networks of potent extracts reveal the potential of unidentified metabolites through node clustering. Also, strain identification studies have proven that all potent isolates belong to the genus Streptomyces. Notably, two extracts (involving leucomycin A1 or K-41 A) demonstrated strong synergy with oxacillin against MRSA, while three extracts (containing staurosporine or bafilomycin C1) showed agonist effects with fluconazole against resistant Candida albicans, indicating potential for combination therapy. This study highlights the marine-derived Streptomyces from the Aegean coasts as a promising resource for the discovery of antimicrobial agents against resistant pathogens. Further bioactivity-guided isolation studies are ongoing to characterize the active constituents.