Re-evaluation and a Structure-Activity Relationship Study for the Selective Anti-anaerobic Bacterial Activity of Luminamicin toward Target Identification.

Luminamicin ( 1 ) isolated in 1985, is a macrodiolide compound exhibiting selective antibacterial activity against anaerobes. However, the antibacterial activity of 1 was not fully examined. In this research, re-evaluation of the antibacterial activity of 1 revealed that 1 is a narrow spectrum and potent antibiotic against Clostridioides difficile ( C. difficile ) and effective against fidaxomicin resistant C. difficile strain. This prompted us to obtain luminamicin resistant C. difficile strains for the determination of the molecular target of 1 in C. difficile . Sequence analysis of 1 -resistant C. difficile indicated that the mode of action of 1 differs from that of fidaxomicin. This is because no mutation was observed in RNA polymerase and mutations were observed in a hypothetical protein and cell wall protein. Furthermore, we synthesized derivatives from 1 to study the structure-activity relationship. This research indicated that the maleic anhydride and the enol ether moieties seem to be pivotal functional groups to maintain the antibacterial activity against C. difficile and the 14-membered lactone may contribute to taking an appropriate molecular conformation.