Ilamycin E and ilamycin F are dual inhibitors of ClpX and ClpC1 in mycobacteria
Abstract The Clp protease system, which is crucial for maintaining protein homeostasis in mycobacteria, has become a promising target. Numerous non-ribosomal natural cyclic peptides, including ilamycins, have been reported to possess antitubercular activities by targeting the ClpC1 component of the ClpC1P1P2 proteasome. In this study, we found that ilamycin E and F (ILE/F) exhibit significantly more potent mycobactericidal activities than other ilamycin components by targeting both ClpX and ClpC1 components of the ClpC1P1P2 and ClpXP1P2 complexes. To our knowledge, this is the first report on the killing of mycobacteria by compounds through the targeting of ClpX. ILE/F have delayed antimicrobial activities and show synergistic or additive activities with many antituberculosis drugs againstMycobacterium tuberculosis, which is consistent with their mechanisms of action. Novel insertion mutations inclpC1, in addition to previously reported mutations, and a unique mutation inclpXhave been identified and proven to cause resistance to ILE/F in mycobacteria. ILE markedly impedes the proteolytic function of the ClpC1P1P2 complex and may disrupt the function of the ClpXP1P2 complex by binding to ClpX. ILE/F are highly effective against mycobacteria by targeting both the ClpC1P1P2 and ClpXP1P2 complexes, highlighting the Clp complexes as promising potent targets, especially through a dual-targeting strategy..
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 08. März Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Gao, Yamin [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2024.02.24.581832 |
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| PPN (Katalog-ID): |
XBI042648378 |
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| 520 | |a Abstract The Clp protease system, which is crucial for maintaining protein homeostasis in mycobacteria, has become a promising target. Numerous non-ribosomal natural cyclic peptides, including ilamycins, have been reported to possess antitubercular activities by targeting the ClpC1 component of the ClpC1P1P2 proteasome. In this study, we found that ilamycin E and F (ILE/F) exhibit significantly more potent mycobactericidal activities than other ilamycin components by targeting both ClpX and ClpC1 components of the ClpC1P1P2 and ClpXP1P2 complexes. To our knowledge, this is the first report on the killing of mycobacteria by compounds through the targeting of ClpX. ILE/F have delayed antimicrobial activities and show synergistic or additive activities with many antituberculosis drugs againstMycobacterium tuberculosis, which is consistent with their mechanisms of action. Novel insertion mutations inclpC1, in addition to previously reported mutations, and a unique mutation inclpXhave been identified and proven to cause resistance to ILE/F in mycobacteria. ILE markedly impedes the proteolytic function of the ClpC1P1P2 complex and may disrupt the function of the ClpXP1P2 complex by binding to ClpX. ILE/F are highly effective against mycobacteria by targeting both the ClpC1P1P2 and ClpXP1P2 complexes, highlighting the Clp complexes as promising potent targets, especially through a dual-targeting strategy. | ||
| 650 | 4 | |a Biology |7 (dpeaa)DE-84 | |
| 650 | 4 | |a 570 |7 (dpeaa)DE-84 | |
| 700 | 1 | |a Fang, Cuiting |0 (orcid)0000-0002-8045-3098 |4 aut | |
| 700 | 1 | |a Zhou, Biao |0 (orcid)0000-0003-1641-4382 |4 aut | |
| 700 | 1 | |a Hameed, H.M. Adnan |0 (orcid)0000-0003-1993-9547 |4 aut | |
| 700 | 1 | |a Sun, Changli |4 aut | |
| 700 | 1 | |a Tian, Xirong |0 (orcid)0000-0003-1184-7875 |4 aut | |
| 700 | 1 | |a He, Jing |4 aut | |
| 700 | 1 | |a Han, Xingli |4 aut | |
| 700 | 1 | |a Zhang, Han |4 aut | |
| 700 | 1 | |a Ju, Jianhua |4 aut | |
| 700 | 1 | |a Chen, Xinwen |4 aut | |
| 700 | 1 | |a Zhong, Nanshan |4 aut | |
| 700 | 1 | |a Ma, Junying |4 aut | |
| 700 | 1 | |a Xiong, Xiaoli |0 (orcid)0000-0002-4632-9122 |4 aut | |
| 700 | 1 | |a Zhang, Tianyu |0 (orcid)0000-0001-5647-6014 |4 aut | |
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