Potent Bactericidal Antimycobacterials Targeting the ChaperoneClpC1 Based on the Depsipeptide Natural Products Ecumicin and Ohmyungsamycin A

Ohmyungsamycin A and ecumicin are structurally related cyclic depsipeptide natural products that possess activityagainstMycobacterium tuberculosis(Mtb), the causative agent oftuberculosis (TB). Herein, we describe the design and synthesis ofa library of analogues of these two natural products using anefficient solid-phase synthesis and late-stage macrolactamizationstrategy. Lead analogues possessed potent activity against Mtb invitro (minimum inhibitory concentration 125-500 nM) and wereshown to inhibit protein degradation by the mycobacterial ClpC1-ClpP1P2 protease with an associated enhancement of ClpC1ATPase activity. The most promising analogue from the seriesexhibited rapid bactericidal killing activity against Mtb, capable ofsterilizing cultures after 7 days, and retained bactericidal activity against hypoxic non-replicating Mtb. This natural product analoguewas also active in an in vivo zebrafish model of infection