Triterpene sapogenin–polyarginine conjugates exhibit promising antibacterial activity against Gram-positive strains

Abstract

Triterpene sapogenins are a group of biologically active compounds with antibacterial activity. However, the limited solubility and poor bioavailability of triterpene sapogenins restrict their therapeutic application. Polyarginine peptides are small cationic peptides with high affinities for multiple negatively charged cell membranes and possess moderate antibacterial activities. In this study, we designed and synthesized a series of sapogenin-polyarginine conjugates in which the triterpene sapogenin moiety was covalently appended to the positively charged polyarginine via click chemistry. A clear synergistic effect was found, and the conjugates exhibited potent and selective antibacterial activity against Gram-positive strains. Among them, BAc-R3 was the most promising compound, which was also proven to be nontoxic toward mammalian cells as well as stable in plasma. The mechanism of BAc-R3 primarily involves an interaction with the bacterial membrane, similar to that of antimicrobial peptides (AMPs). This scaffold design opens an avenue for the further development of novel antibiotics comprised of the combination of a peptide and a natural product.

Oligo(para-phenylenes)s–Oligoarginine Conjugates as Effective Antibacterial Agents with High Plasma Stability and Low Hemolysis

“…The bacterial cells were washed three times with PBS, fixed with 3% glutaraldehyde/PBS solution at 4 °C overnight, washed several times with PBS, and then fixed with 1% osmic acid at 4 °C for 1 h. After washing three times with PBS, the bacterial samples were dehydrated with a series of graded ethanol and acetone. The samples were added into a solution containing acetone and Epon resin (1:1, v/v) for 30 min, then buried with Epon resin overnight . The samples were sectioned using an ultramicrotome, stained with uranyl acetate and lead citrate for 10 min, and visualized using TEM (Hitachi H-7650 microscope, Japan).…”

“…Nontoxic control was carried out using PBS without any conjugates, and each assay was repeated five times. Cell viability was finally calculated by the relative ratio of the absorbance values in the treated and nontoxic control groups …”

“…Next, 90 μL of the erythrocyte suspension was added to wells containing 10 μL of the solution of each conjugate and incubated for 1 h at 37 °C. Then, the plate was centrifuged at 3000 rpm for 5 min, and the supernatant (50 μL) was then transferred to another 96-well plate containing 50 μL of PBS . Hemolytic activity was determined by OD 405nm using a SpectraMax M5 spectrophotometer.…”

“…Besides, Na and co-workers reported a series of triterpene sapogenin–polyarginine conjugates, which showed promising antibacterial activity. Bac-R 3 showed the highest antibacterial activity among these amphiphilic conjugates, indicating that appropriate equilibrium between the hydrophobic component and hydrophilic polyarginine is crucial for the antibacterial activity of AMP analogues . As a mimic of AMP, the conjugates with net positive charges tended to interact with the negatively charged bacterial membrane rather than zwitterionic mammalian membranes .…”

Alisma genus: Phytochemical constituents, biosynthesis, and biological activities

“…Protostane‐type triterpenoind is an isomer of dammarane‐type triterpenoids, featuring α ‐configurations of 8‐CH 3 and 13‐H, and β ‐configurations of 9‐H and 14‐CH 3 . As characteristic constituents of the genus Alisma (Hur, Choi, & Park, 2007; Jiang et al, 2006), protostane‐type triterpenoids have a variety of functions, such as anti‐inflammatory, antibacterial, antioxidation, and antitumor activities (Na et al, 2016; Xu, Wang, Pu, Tao, & Zhang, 2018; Zhang, Men, & Lei, 2014).…”