<jats:title>Abstract</jats:title><jats:p>Neo-actinomycins A and B (1 and 2), two new natural actinomycins featuring an unprecedented tetracyclic 5<jats:italic>H</jats:italic>-oxazolo[4,5-<jats:italic>b</jats:italic>]phenoxazine chromophore, were isolated from the marine-derived actinomycete<jats:italic>Streptomyces</jats:italic>sp. 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 (IC<jats:sub>50</jats:sub>: 38.7 and 65.8 nM, respectively) and moderate antibacterial activities against methicillin-resistant<jats:italic>Staphylococcus aureus</jats:italic>(MRSA) and vancomycin-resistant<jats:italic>Enterococci</jats:italic>(VRE) strains.