Design, Synthesis and Biological Evaluation of Bengamide Analogues as ClpP Activators

To combat multidrug-resistant Gram-positive bacteria, new antimicrobials particularly those with novel mechanism of action are badly needed. Different with conventional antibiotics which are typical inhibitors, small-molecule activators of bacterial ClpP represent a new class of antibiotics. No ClpP activator has been developed for clinical trial. Herein, we conducted a screening on our library of bengamide-like ring-opened analogues and found that L472-2 possesses a low minimum inhibitory concentration (MIC) against S.aureus and shows no activity for ClpP activation in vitro, but it displayed reduced antibacterial activity against S. aureus with clpP deletion. In order to obtain bengamide analogues that activate ClpP in vitro as well as possess antibacterial activity, we perform further structural modifications starting from L472-2. Compound 37 remains the antimicrobial activity and activation of ClpP protein in vitro, which could be viewed as a new chemical scaffold for ClpP activators and worthy of further investigation.