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.



Redirecting the pioneering function of FOXA1 with covalent small molecules

Sang Joon Won, Yuxiang Zhang, Christopher J. Reinhardt,Lauren M. Hargis, Nicole S. MacRae,Kristen E. DeMeester,Evert Njomen,Jarrett R. Remsb...