Potent Bactericidal Antimycobacterials Targeting the Chaperone ClpC1 Based on the Depsipeptide Natural Products Ecumicin and Ohmyungsamycin A

Ohmyungsamycin
A and ecumicin are structurally related cyclic depsipeptide
natural products that possess activity against Mycobacterium
tuberculosis (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.