Potent Bactericidal Antimycobacterials Targeting the Chaperone ClpC1 Based on the Depsipeptide Natural Products Ecumicin and Ohmyungsamycin A.
Hawkins PME, Hoi DM, Cheung CY, Wang T, Quan D, Sasi VM, Liu DY, Linington RG, Jackson CJ, Oehlers SH, Cook GM, Britton WJ, Clausen T, Payne RJ.
Ohmyungsamycin A and ecumicin are structurally related cyclic depsipeptide natural products that possess activity against <i>Mycobacterium tuberculosis</i> (Mtb), the causative agent of tuberculosis (TB). Herein, we describe the design and synthesis of a library of analogues of these two natural products using an efficient solid-phase synthesis and late-stage macrolactamization strategy. Lead analogues possessed potent activity against Mtb in vitro (minimum inhibitory concentration 125-500 nM) and were shown to inhibit protein degradation by the mycobacterial ClpC1-ClpP1P2 protease with an associated enhancement of ClpC1 ATPase activity. The most promising analogue from the series exhibited rapid bactericidal killing activity against Mtb, capable of sterilizing cultures after 7 days, and retained bactericidal activity against hypoxic non-replicating Mtb. This natural product analogue was also active in an in vivo zebrafish model of infection.