Neo-actinomycins A and B (1 and 2), two new natural actinomycins featuring an unprecedented tetracyclic 5H-oxazolo[4,5-b]phenoxazine chromophore, were isolated from the marine-derived actinomyceteStreptomycessp. IMB094. Their structures were elucidated by spectroscopic analyses. The presence of this ring system was proposed to originate from a condensation between actinomycin D (3) with α-ketoglutarate and pyruvate, respectively. Compound 1 showed potent cytotoxic activities against human cancer HCT116 and A549 cell lines in the nanomolar range (IC₅₀: 38.7 and 65.8 nM, respectively) and moderate antibacterial activities against methicillin-resistantStaphylococcus aureus(MRSA) and vancomycin-resistantEnterococci(VRE) strains.