Total Synthesis of 9-dechlorochrysophaentin Reveals a Novel Mechanism of Inhibiting Cell Wall Biosynthesis

Abstract

Antibiotic resistance is now known for every clinically prescribed antibiotic, which means new antibiotics with novel mechanisms of action are needed. Historically natural products have served as a source of new antimicrobial agents and/or aid the identification of novel pathogen targets. As a result, the majority of approved antimicrobial therapeutics are either natural products or derived from natural products. Chrysophaentin A, a marine natural product isolated from the alga Chrysophaeum taylori, exhibits micromolar activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA). The mechanism of action of this natural antimicrobial agent was believed to be associated with the inhibition of FtsZ, a key cellular division protein. Unfortunately, further study of chrysophaentin A has been hampered due to limited supply by isolation from its marine source. Total synthesis of chrysophaentin A will not only allow further study of its mechanism of action but also access to other analogs for further development. As described in this dissertation we have developed chemical syntheses of four chrysophaentin A congeners, lacking only a chloro group at C9 relative to chrysophaentin A. Key steps in our total synthesis include a Lewis acid promoted O to C alkyl group migration, a cis-selective ring-closing metathesis ring-closure and stereoselective construction of a peripheral trisubstituted chloroalkene. When evaluated against several clinically relevant pathogens our synthetic congeners exhibited antimicrobial activity comparable or slightly superior to chrysophaentin A. Finally, cell imaging experiments support a mechanism of action more complex than direct FtsZ inhibition. Chrysophaentin A and 9-dechlorochrysophaentin derivatives indirectly inhibit cell wall biosynthesis by delocalization of FtsZ, FtsA, and PBP2b. Future work will be directed towards the total synthesis of chrysophaentin A and additional analogs, as well as, efforts towards target identification.