Synthesis, Antibacterial Activity, and Nephrotoxicity of Polymyxin B Analogues Modified at Leu-7, d-Phe-6, and the N-Terminus Enabled by S-Lipidation.

With the post-antibiotic era rapidly approaching, many have turned their attention to developing new treatments, often by structural modification of existing antibiotics. Polymyxins, a family of lipopeptide antibiotics that are used as a last line of defense in the clinic, have recently developed resistance and exhibit significant nephrotoxicity issues. Using thiol-ene chemistry, the facile preparation of six unique S-lipidated building blocks was demonstrated and used to generate lipopeptide mimetics upon incorporation into solid-phase peptide synthesis (SPPS). We then designed and synthesized 38 polymyxin analogues, incorporating these unique building blocks at the N-terminus, or to replace hydrophobic residues at positions 6 and 7 of the native lipopeptides. Several polymyxin analogues bearing one or more S-linked lipids were found to be equipotent to polymyxin, showed minimal kidney nephrotoxicity, and demonstrated activity against several World Health Organisation (WHO) priority pathogens. The S-lipidation strategy has demonstrated potential as a novel approach to prepare innovative new lipopeptide antibiotics.

Intestinal metabolite compound K of ginseng saponin potently attenuates metastatic growth of hepatocellular carcinoma by augmenting apoptosis via a Bid-mediated mitochondrial pathway.

It was recently shown that compound K (CK), an intestinal bacterial metabolite of ginseng saponin, exhibits antihepatocellular carcinoma (HCC) activity, and Bid is a potential drug target for HCC therapy. This paper reports a novel mechanism of CK-induced apoptosis of HCC cells via Bid-mediated mitochondrial pathway. CK dramatically inhibited HCC cells growth in concentration- and time-dependent manners, and a high dose of CK could induce HCC cell apoptotic cell death. Furthermore, the effective dose of CK potently attenuated the subcutaneous tumor growth and spontaneous HCC metastasis in vivo. At the molecular level, immunohistochemical staining revealed that Bid expression in subcutaneous tumor and liver metastasis tissues decreased dramatically in CK-treated groups compared to untreated controls, which also implies that Bid may play a critical role in the growth and progression of HCC. Further study shows that translocation of full-length Bid to the mitochondria from nuclei during cytotoxic apoptosis was associated with the release of cytochrome c from mitochondria, indicating that full-length Bid is sufficient for the activation of mitochondrial cell death pathways in response to CK treatment in HCC cells. Taken together, the results not only reveal a Bid-mediated mitochondrial pathway in HCC cells induced by CK but also suggest that CK may become a potential cytotoxic drug targeting Bid in the prevention and treatment of HCC.