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The reemergence of infectious diseases and resistant pathogens represents a serious problem for human life. Hence, the screening for new or alternative antimicrobial compounds is still urgent. Unusual ecosystems such as saline habitats are considered promising environments for the purposes of isolating bacterial strains able to produce potent natural products. The aim of this study is the identification of bioactive compounds biosynthesized by three halotolerant strains isolated from the Sebkha of Oran (Algeria) using gas chromatography coupled to mass spectrometry. Primary screening investigation of antimicrobial activities were performed against reference bacterial and fungal strains and revealed a broad-spectrum activity. Secondary metabolite extraction was carried out using ethyl acetate and chloroform. Crude extracts were tested for bioactivity using the disc diffusion method and subjected to GC-MS analysis. The extracts showed an important inhibitory effect against all tested strains. Fifty-six compounds were identified; they include tert-butyl phenol compounds, fatty acid methyl esters due to the methylation procedure, hydrocarbons, aldehydes, benzoquinones, pyrrols, and terpenes. Literature reports such compounds to have wide biological and pharmaceutical applications. The molecular identification of the three isolates was achieved using the 16S-23S rRNA gene intergenic spacer region (ITS) and 16S rRNA sequencing. Partial 16S rRNA gene sequencing showed very high similarity with many species of Bacillus. This study provided insights on the potential of halotolerant Bacillus as drug research target for bioactive metabolites. The findings suggest that the Great Sebkha of Oran is a valuable source of strains exhibiting variety of beneficial attributes that can be utilized in the development of biological antibiotics., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)