Polycyclic tetramate macrolactams (PTMs) are widely distributed in nature and are generated from a compact biosynthetic pathway. Bioinformatics analysis of the draft genome sequence of marine-derived Streptomyces sp. SCSIO 40060 revealed the presence of a putative PTM-encoding biosynthetic gene cluster (BGC). Comparison of this PTM BGC with those from the databank by genome mining suggests that Streptomyces sp. SCSIO 40060 should produce PTMs with a 5/6/5 type of carbocyclic ring. Subsequently, a 40-L scale of cultivation of Streptomyces sp. SCSIO 40060 led to the isolation and characterization of four known PTMS, ikarugamycin (1), epoxyikarugamycin (2), capsimycin (3), capsimycin C (4), and three new PTMs, hydroxyikarugamycins AeC (5e7). The planar structures of 5e7 were assigned by comprehensive spectroscopic analysis and the absolute configurations of 5 and 6 were unequivocally determined by X-ray diffraction analysis. The absolute structure of 7 was deduced by comparing ECD spectra of 5e7. Capsimycin (3) showed antimicrobial activity against methicillin-resistant Staphylococcus aureus with a MIC value of 16 mg/mL and displayed cytotoxicity against several cancer cell lines with IC50 values ranging from 2.62 to 6.87 mM.