<p>Analysis of an antimicrobial extract prepared from culture broth of the marine-derived actinomycete <i>Streptomyces</i> sp. G278 led to the isolation of ten compounds, <b>1</b>-<b>10</b>. Two compounds, 2,5-Bis(5-<i>tert</i>-butyl-2-benzoxazolyl)thiophene (<b>1</b>), and 3-hydroxyl-2-methylpyridine (<b>2</b>) were isolated from a natural source for the first time. The structures of the isolated compounds were established by their spectral data analysis, including mass spectrometry, 1D-NMR, 2D-NMR, and X-ray crystallographic analysis in case of compound <b>3</b>. All isolated compounds were evaluated for their antimicrobial activity against a panel of clinically significant microorganisms. Compounds <b>1</b> and <b>3</b> selectively inhibited <i>Enterococcus faecalis</i> (MIC: 256 μg/mL). Compound <b>2</b> was found to have antibacterial and antifungal activity against <i>Escherichia coli</i> (MIC: 64 μg/mL), <i>Salmonella enterica</i> (MIC: 256 μg/mL), <i>Staphylococcus aureus</i> (MIC: 256 μg/mL), <i>Enterococcus faecalis</i> (MIC: 256 μg/mL), and <i>Candida albicans</i> (MIC: 64 μg/mL). Except for compounds <b>9</b> and <b>10</b>, the other known metabolites (<b>4</b>-<b>8</b>) also exhibited antimicrobial activity.</p
