Total Synthesis of Xanthoangelol B and Its Various Fragments: Toward 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 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.

Recent Advances in Histidine Kinase-Targeted Antimicrobial Agents

“…Based on the measurements from SDS-PAGE autoradiography and the effects on phosphotransferase (PT) activity of SaeS, both compounds displayed a specific inhibition on HK activity of SaeS, with IC 50 values of 220 and 160 μM for xanthoangelol B and PM-56, respectively. In additon, Xanthoangelol B and PM-56 could also inhibit another HK, AgrC, with IC 50 of 339 and 140 μM, respectively, indicating the possibility that xanthoangelol B scaffold could be further developed as a broad-spectrum HK inhibitor despite the IC 50 values higher than expected (Mizar et al, 2018).…”

“…In S. aureus , SaeRS is composed of the HK SaeS, RR SaeR, and two auxiliary proteins SaeP and SaeQ. The TCS is regarded as a master virulence regulator because it controls the production of over 20 virulence factors, such as hemolysins, leukocidins, superantigens, surface proteins, and proteases ( Liu et al, 2016 ; Mizar et al, 2018 ).…”

“…Xanthoangelol B was screened out by Mizar et al (2018) using a GFP (Green fluorescent protein) reporter system they developed previously to screen plant-derived SaeRS inhibitors ( Yeo et al, 2018 ). The compound has been synthesized at present, and a derivative named PM-56 was obtained during the synthesis.…”

“…Xanthoangelol B and PM-56 showed excellent inhibitory activities against SaeRS, with IC 50 s against the SaeRS GFP reporter at 2.1 and 4.3 μM, respectively. Significant transcriptional suppression of four downstream virulence genes [α-hemolysin ( hla ), aureolysin ( aur ), γ-hemolysin, and staphylokinase] were observed, which further implied the action of both compounds on the SaeRS pathway and their possibility of development as antivirulence agents ( Mizar et al, 2018 ).…”

Roles of Two-Component Systems in Pseudomonas aeruginosa Virulence

“…Antimicrobial resistance (AMR) has become a serious global health threat because the rapid emergence of AMR has led to considerable increase in morbidity and mortality across the world [1][2][3][4]. Consequently, it is critical to develop new antibiotics or alternative therapeutic strategies to address pathogen antimicrobial resistance [5][6][7]. The increase of multi-drug resistant (MDR), pan-drug resistant (PDR), and extensively drug-resistant (XDR) isolates of P. aeruginosa constitute a substantial therapeutic challenge [8].…”