Neoabyssomicin A (1) possessing a caged 6/6/6 ring system fused with two additional 6/9 lactone rings, neoabyssomicin B (2) featuring a 12-membered macrolactone ring and its seco-form, neoabyssomicin C (3), along with the known abyssomicin 2 (4) and 4 (5), were discovered from the deep-sea derived Streptomyces koyangensis SCSIO 5802. The structures of 1–3 were elucidated on the basis of MS, NMR spectroscopic and X-ray diffraction data analyses. A plausible biogenetic relationship of 1–5 is proposed. Additionally, compound 4 shows antibacterial activities against a panel of Gram-positive pathogens, including clinical MRSA strains, with MICs of 3–15 μg/mL; compounds 1 and 3 also were found to augment HIV-1 virus replication in a human lymphocyte model.