Our investigations into the anti-TB properties of the South China Sea deep-sea Verrucosispora sp. (MS100128) led to the isolation, identification, and anti-TB evaluation of new (1–3) and known (4–6, 10) abyssomicins. Structures were assigned to 1–3 on the basis of detailed spectroscopic analysis, biosynthetic considerations, mechanistic studies, and semisynthesis from the co-metabolite 5. Detailed analytical studies into abyssomicin Michael addition chemistry informed our understanding of the chemical reactivity, stability, and anti-TB properties of this rare structure class. We established 8 as a far more potent Michael acceptor than 5, and used this to rationalize its superior antibacterial properties. We transformed 5 into the Michael adduct 1 and used both in vitro and cell-based analytical studies to demonstrate that 1 can act as a prodrug, thus responding to oxidative activation to selectively deliver the anti-TB antibiotic 8.
Our studies make a contribution beyond the specifics of the abyssomicin pharmacophore by drawing attention to the possible utility of thioether Michael addition adducts as a means to stabilize highly reactive Michael acceptors, thereby enhancing bioavailability and improving therapeutic potential. The thioether Michael adduct prodrug concept, inspired by abyssomicins from the South China Sea, offers a promising new approach to “chemically package” bioactive Michael acceptors, thus improving their chances of being developed into clinically useful drugs.