The incidence of drug-resistant bacterial infections is increasing, posing a serious threat to human health. Marine natural products are a rich source of bioactive molecules, and the obligate marine actinomycete genus Salinispora has yielded structurally diverse compounds including salinosporamide A. To discover new antibiotics from S. arenicola strains, we used a rifampin-resistant MRSA strain to screen for antibiotic activities derived from non-rifamycin compounds. We screened approximately 2400 crude extracts from a Salinispora-enriched library, with only six (0.3%) showing activity against rifampin-resistant MRSA. From S. arenicola strain CNR-647, an unknown quinone-like metabolite was isolated as a new antibiotic, arenimycin, which belongs to the benzo[a]naphthacene quinone class and is most closely related to SF2446B1 (with a hydroxyl instead of methoxyl group at the 4¢-position of the sugar). This is the first report of this class of antibiotics from S. arenicola. Herein, we report the isolation, structure elucidation, and potent antibiotic activity of arenimycin against a panel of drug-resistant human pathogens.