For many multiresistant Gram-positive bacteria (e.g., methicillin-resistant Staphylococcus aureus strains, MRSA), vancomycin- or teicoplanin-type glycopeptide antibiotics are the sole remaining means of treatment. Thus, efforts have been directed towards discovering novel antibiotics from nature (especially microorganisms from previously unexplored habitats) and targeting biosynthetic processes absent in humans, such as p-aminobenzoate (pABA) biosynthesis (part of tetrahydrofolate biosynthesis). In this context, we focused on rare actinomycetes from the deep-sea plain and screened them for inhibitors of pABA biosynthesis. We isolated Verrucosispora strain AB 18-032 from a sediment sample collected in the Japanese Sea at a depth of 289 m. Here, we describe new polycyclic polyketide-type antibiotics named abyssomicins, which are produced by this strain and represent the first known bacterial-derived inhibitors of pABA biosynthesis. Compounds 1–3 (abyssomicins B, C, and D) were purified via size-exclusion, adsorption chromatography, and preparative reversed-phase HPLC, then characterized by high-resolution ESI-FTICR mass spectrometry, 1D/2D NMR spectroscopy, and X-ray crystallography. Their structures include multiple ring systems (four for 2, five for 1 and 3), an oxabicyclooctane system (rings C and D), and stereocenters (the absolute configuration at C(11) of 3 was determined via Mosher and Helmchen methods, with analogous configurations assumed for 1 and 2). Only abyssomicin C (2) showed antibiotic activity against Gram-positive bacteria, with minimal inhibition concentrations of 4 µg/mL against MRSA and 13 µg/mL against a vancomycin-resistant S. aureus strain. Structural analysis revealed striking similarities between the oxabicyclooctane system of abyssomicins and the solution conformation of chorismate (a precursor to pABA) as well as synthetic transition-state analogues of chorismate mutase inhibitors. The presence of a Michael system (C(7)–C(9)) in active abyssomicin C (absent in inactive 1 and 3) strongly indicates its significance for antibiotic activity. We hypothesize that abyssomicin C mimics chorismate and covalently traps the target enzyme via nucleophilic amino acid side chains, thereby inhibiting pABA biosynthesis from chorismate. Further investigations on abyssomicin biosynthesis, exact target enzyme determination, and mode of action are currently in progress.