Acyldepsipeptide Antibiotics and a Bioactive Fragment Thereof Differentially Perturb Mycobacterium tuberculosis ClpXP1P2 Activity in Vitro
| Autor: | Jason K. Sello, Shashank Gupta, Robert T. Sauer, Emma L. Handy, Corey L. Compton, William R. Bishai, Karl R. Schmitz |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Proteases biology 010405 organic chemistry General Medicine biology.organism_classification 01 natural sciences Biochemistry In vitro 0104 chemical sciences Microbiology Mycobacterium tuberculosis Acyldepsipeptide antibiotics 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology chemistry Drug development Molecular Medicine Pharmacophore Pathogen Function (biology) |
| Zdroj: | ACS Chemical Biology. 18:724-733 |
| ISSN: | 1554-8937 1554-8929 |
| DOI: | 10.1021/acschembio.9b00454 |
| Popis: | Proteolytic complexes in Mycobacterium tuberculosis (Mtb), the deadliest bacterial pathogen, are major foci in tuberculosis drug development programs. The Clp proteases, which are essential for Mtb viability, are high priority targets. These proteases function through the collaboration of ClpP1P2, a barrel-shaped heteromeric peptidase, with associated ATP-dependent chaperones like ClpX and ClpC1 that recognize and unfold specific substrates in an ATP-dependent fashion. The critical interaction of the peptidase and its unfoldase partners is blocked by the competitive binding of acyldepsipeptide antibiotics (ADEPs) to the interfaces of the ClpP2 subunits. The resulting inhibition of Clp protease activity is lethal to Mtb. Here, we report the surprising discovery that a fragment of the ADEPs retains anti-Mtb activity, yet stimulates rather than inhibits the ClpXP1P2-catalyzed degradation of proteins. Our data further suggest that the fragment stabilizes the ClpXP1P2 complex and binds ClpP1P2 in a fashion distinct from the intact ADEPs. A structure-activity relationship study of the bioactive fragment defines the pharmacophore and points the way towards the development of new drug leads for the treatment of tuberculosis. |
| Databáze: | OpenAIRE |
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