Total Synthesis of Xanthoangelol B and Its Various Fragments: Toward Inhibition of Virulence Factor Production of Staphylococcus aureus.

Pushpak Mizar,Truc Kim,Soyoung Cha,Seung Seo Lee,Kyoung-Seok Ryu,Taeok Bae,Kyeong Kyu Kim,Rekha Arya,Dae Wook Kim,Won-Sik Yeo,Ki Hun Park

doi:10.1021/acs.jmedchem.8b01012

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 antivirulence 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.

Highlights

Antibiotic resistance has arisen as an extremely serious health problem in all parts of the world
methicillin-resistant Staphylococcus aureus (MRSA) is a nosocomial and communal menace that is resistant to many antibacterial drugs and antiseptics.[3−5] The U.S Centers for Disease Control and Prevention recently issued a report to various governments and organizations outlining the concern about MRSA
Xanthoangelol B 1 can be disconnected to two main fragments: fragment 3 and 4-hydroxybenzaldehyde 2

Summary

■ INTRODUCTION

Antibiotic resistance has arisen as an extremely serious health problem in all parts of the world. Compounds 1 and PM-56 treated groups showed comparable reduction in CFU by 76.8% and 83.3%, respectively (Figure S7B) Together, these results suggest that the protection effects initiated by the saeS knockout were not drastically improved by the treatment with 1 and PM-56, and subsequently, the activities of both compounds on G. mellonela were relevant to Article domain of SaeS. An inhibitor binding this domain has the potential to be a broad-spectrum antibacterial agent.[15] many efforts have been made to discover such a class of inhibitors, with some degree of success.[15,43,44] Compounds 1 and PM-56 displayed excellent SaeRS-related antivirulence activity in vitro and in vivo These results were comparable to the effects seen in saeS knockout studies. Regardless, our data provide a strong starting point for further optimization

■ CONCLUSION

■ ACKNOWLEDGMENTS

■ REFERENCES