Monday, December 4, 2023

Structure of Staphylococcus aureus ClpP Bound to the Covalent Active Site Inhibitor Cystargolide A

Illigmann, AstridVielberg, Marie-TheresLakemeyer, MarkusWolf, FelixDema, TaulantStange, PatrikKuttenlochner, WolfgangLiebhart, ElisaKulik, AndreasStaudt, NicoleMalik, ImranGrond, StephanieSieber, Stephan A.Kaysser, LeonardGroll, MichaelBrötz-Oesterhelt, HeikeAngew. Chem. Int. Ed. 2023, e202314028.

https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.202314028

The caseinolytic protease is a highly conserved serine protease, crucial to prokaryotic and eukaryotic protein homeostasis, and a promising antibacterial and anticancer drug target. Here, we describe the potent cystargolides as the first natural β-lactone inhibitors of the proteolytic core ClpP. Based on the discovery of two clpP genes next to the cystargolide biosynthetic gene cluster in Kitasatospora cystarginea, we explored ClpP as a potential cystargolide target. We show the inhibition of Staphylococcus aureus ClpP by cystargolide A and B by different biochemical methods in vitro. Synthesis of semi-synthetic derivatives and probes with improved cell penetration allowed us to confirm ClpP as a specific target in S. aureus cells and to demonstrate the anti-virulence activity of this natural product class. Crystal structures show cystargolide A covalently bound to all 14 active sites of ClpP from S. aureus, Aquifex aeolicus, as well as Photorhabdus laumondii, and reveal the molecular mechanism of ClpP inhibition by β-lactones, the pioneering group of ClpP inhibitors.



Mutant-selective AKT inhibition through lysine targeting and neo-zinc chelation

Gregory B. Craven, Hang Chu, Jessica D. Sun, Jordan D. Carelli, Brittany Coyne, Hao Chen, Ying Chen, Xiaolei Ma, Subhamoy Das, Wayne Kong, A...