Total Synthesis and Biological Evaluation of Modified Ilamycin Derivatives
2022
Jennifer Greve | Axel Mogk | Uli Kazmaier
Ilamycins/rufomycins are marine cycloheptapeptides containing unusual amino acids. Produced by <i>Streptomyces</i> sp., these compounds show potent activity against a range of mycobacteria, including multidrug-resistant strains of <i>Mycobacterium tuberculosis</i>. The cyclic peptides target the AAA+ protein ClpC1 that, together with the peptidases ClpP1/ClpP2, forms an essential ATP-driven protease. Derivatives of the ilamycins with a simplified tryptophane unit are synthesized in a straightforward manner. The ilamycin derivative <b>26</b> with a cyclic hemiaminal structure is active in the nM-range against several mycobacterial strains and shows no significant cytotoxicity. In contrast, derivative <b>27</b>, with a glutamic acid at this position, is significantly less active, with MICs in the mid µM-range. Detailed investigations of the mode of action of <b>26</b> indicate that <b>26</b> deregulates ClpC1 activity and strongly enhances ClpC1-WT ATPase activity. The consequences of <b>26</b> on ClpC1 proteolytic activities were substrate-specific, suggesting dual effects of <b>26</b> on ClpC1-WT function. The positive effect relates to ClpC1-WT ATPase activation, and the negative to competition with substrates for binding to the ClpC1 NTD.
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