Two Novel Phenylpropanoid Trimers From Ligusticum chuanxiong Hort With Inhibitory Activities on Alpha-Hemolysin Secreted by Staphylococcus aureus

Abstract

The emergence of antibiotic resistance in Staphylococcus aureus has necessitated the development of innovative anti-infective agents acting on novel targets. Alpha-hemolysin (Hla), a key virulence factor of S. aureus, is known to cause various cell damage and death. In this study, with bioassay-guided fractionation, a pair of unusual epimeric lignan trimers, ligustchuanes A and B (1 and 2), were isolated from the rhizomes of Ligusticum chuanxiong Hort, together with two known phthalides being identified by UPLC-QTOF-MS. To the best of our knowledge, trimers with rare C8-C9″-type neolignan and ferulic acid fragments have not been identified in any natural product. Both of them were isolated as racemic mixtures, and their absolute configurations were determined by comparing experimental and calculated ECD spectra after enantioseparation. Ligustchuane B exhibited an outstanding inhibitory effect on α-hemolysin expression in both MRSA USA300 LAC and MSSA Newman strains at concentrations of 3 and 6 μM, respectively. Notably, a mouse model of infection further demonstrated that ligustchuane B could attenuate MRSA virulence in vivo.

Lignan and Phthalide Derivatives from the Rhizome of Ligusticum chuanxiong (Rhizoma chuanxiong) and Evaluation of Their anti-Xanthine Oxidase Activities

“…Structurally, compounds 1 – 3 represent a group of 8′–9-linked neolignans. In particular, lignan featuring a C-8′–C-9-linked skeleton is a rare occurrence in nature, with only around 50 examples of this chemotype reported in the literature. − Moreover, 1 is a novel 9-norneolignan containing a 7, 8′-epoxy tetrahydrofuran ring moiety, while 3 represents the fifth example of phenylpropanoid trimers with 8′-9-type neolignan skeleton . Compounds 4 and 5 are novel phthalide-phenylpropanoid heterodimers, representing a new class of natural products.…”

Bacillus velezensis iturins inhibit the hemolytic activity of Staphylococcus aureus

“…Arg200 is implicated in membrane binding and cell lysis, while Asp183 and Asp185 are involved in cell lysis 65 , 66 . Indeed, several studies have demonstrated the ability of anti-virulence compounds to bind to Trp179 and Arg200, showing the importance of these residues for hemolytic activity 30 – 32 . Another proposed binding model for iturin A1 and hemolysin shows the interaction of the ligand with the protein within the pore structure, which could be a possible mechanism by which iturin blocks the hemolytic activity.…”

“…Therefore, the grid box was designed to focus on this residue. For hemolysin, three grid boxes were designed to cover the amino acid residues described in the literature to interact with other anti-hemolytic compounds 29 – 32 . The grid boxes were built using the following amino acid residues: Grid 01—Tyr102, Arg104, Asn105, Ile107, Asp108, Thr109, Glu111, Tyr112, Met113, Ser114, Leu116, Tyr118, Ile142, Gly143 and His144; Grid 02—Gly126, Asp127, Asp128, and Ile132; Grid 03—Asn176, Gln177, Asn178, Trp179, Gly180, Pro181, Tyr182, Gln194, Leu195, Met197, Lys198, Thr199, and Agr200.…”

Recent advances in the discovery of plant-derived antimicrobial natural products to combat antimicrobial resistant pathogens: insights from 2018–2022

“…Ligustchuanes A and B ( 3 , 4 ) are two novel epimeric lignan trimers containing a unique neolignan linkage, ferulic acid, and ethoxyl groups isolated from the rhizomes of Ligusticum striatum DC., Apiaceae, each in a racemic mixture. 37 Lignans are a structurally diverse group of phenols characterized by β,β′ linkages of phenyl propane units. Diversity stems from varying degrees of side-chain oxidation, diversity of the aromatic ring, or changes in the linkage of the two or more units.…”

“…41 The rhizomes of L. striatum have been traditionally used to treat gynecological diseases, irregular menstruation, amenorrhea, dysmenorrhea, headache, rheumatism arthralgia and hemiplegia caused by stroke, coronary heart disease, and possess anti-inflammatory properties. 37,40,42 Most medicinal preparations with chuanxiong are combined with other plants, commonly Angelica sinensis (Oliv.) Diels (Apiaceae), Paeonia lactiflora Pall.…”