AI Article Synopsis
- Ohmyungsamycin A and ecumicin are cyclic depsipeptides with anti-tuberculosis properties, specifically targeting Mycobacterium tuberculosis (Mtb).
- Researchers created a library of analogues using solid-phase synthesis and a strategy called macrolactamization, leading to strong inhibitory effects against Mtb with minimum concentrations between 125-500 nM.
- The most effective analogue demonstrated rapid bactericidal action, effectively sterilizing Mtb cultures within a week and retaining efficacy against dormant bacteria, also showing effectiveness in a zebrafish infection model.
Article Abstract
Ohmyungsamycin A and ecumicin are structurally related cyclic depsipeptide natural products that possess activity against (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.
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| http://dx.doi.org/10.1021/acs.jmedchem.1c02122 | DOI Listing |
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