Total synthesis of xanthoangelol B and its various fragments: towards inhibition of virulence factor production of Staphylococcus aureus

Abstract

As an alternative strategy to fight antibiotic resistance, two-component systems (TCSs) have emerged as novel targets. Among TCSs, master virulence regulators that control the expression of multiple virulence factors are considered as excellent anti-virulence targets. In Staphylococcus aureus, virulence factor expression is tightly regulated by a few master regulators, including the SaeRS TCS. In this study, we used a SaeRS GFP-reporter system to screen natural compound inhibitors of SaeRS, and identified xanthoangelol B 1, a prenylated chalcone from Angelica keiskei as a hit. We have synthesized 1 and its derivative PM-56, and shown that 1 and PM-56 both had excellent inhibitory potency against the SaeRS TCS, as demonstrated by various in vitro and in vivo experiments. As a mode of action, 1 and PM-56 were shown to bind directly to SaeS and inhibit its histidine kinase activity, which suggests a possibility of a broad spectrum inhibitor of histidine kinases.

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