Feedback

Total Synthesis and Biological Evaluation of Modified Ilamycin Derivatives

Affiliation
Organic Chemistry, Saarland University, Campus Building C4.2, 66123 Saarbruecken, Germany
Greve, Jennifer;
ORCID
0000-0003-3674-5410
Affiliation
Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany
Mogk, Axel;
ORCID
0000-0001-9756-0589
Affiliation
Organic Chemistry, Saarland University, Campus Building C4.2, 66123 Saarbruecken, Germany
Kazmaier, Uli

Ilamycins/rufomycins are marine cycloheptapeptides containing unusual amino acids. Produced by Streptomyces sp., these compounds show potent activity against a range of mycobacteria, including multidrug-resistant strains of Mycobacterium tuberculosis . 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 26 with a cyclic hemiaminal structure is active in the nM-range against several mycobacterial strains and shows no significant cytotoxicity. In contrast, derivative 27 , 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 26 indicate that 26 deregulates ClpC1 activity and strongly enhances ClpC1-WT ATPase activity. The consequences of 26 on ClpC1 proteolytic activities were substrate-specific, suggesting dual effects of 26 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.

Cite

Citation style:
Could not load citation form.

Rights

License Holder: © 2022 by the authors.

Use and reproduction: