Acyldepsipeptide Antibiotics and a Bioactive Fragment Thereof Differentially Perturb Mycobacterium tuberculosis ClpXP1P2 Activity in Vitro.
Acyldepsipeptide Antibiotics and a Bioactive Fragment Thereof Differentially Perturb Mycobacterium tuberculosis ClpXP1P2 Activity in Vitro.
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DOI：
10.1021/acschembio.9b00454
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发表时间：
2023-04-21
影响因子：
4
通讯作者：
Sello JK
中科院分区：
文献类型：
--
作者：
Schmitz KR;Handy EL;Compton CL;Gupta S;Bishai WR;Sauer RT;Sello JK
结核分枝杆菌(Mtb)中的蛋白分解复合体是最致命的细菌病原体，是结核病药物开发计划的主要焦点。对于结核分枝杆菌生存至关重要的CLP蛋白水解酶是高度优先的靶标。这些蛋白水解酶通过桶状异构肽酶ClpP1P2与相关的依赖于ATP的伴侣蛋白(如ClpX和ClpC1)的协作发挥作用，这些伴侣蛋白以依赖于ATP的方式识别和解开特定的底物。酰基多肽抗生素(ADEP)与ClpP2亚基的界面竞争结合，阻断了肽酶与其展开酶伙伴之间的关键相互作用。由此产生的对CLP蛋白酶活性的抑制对结核分枝杆菌是致命的。在这里，我们报告了一个令人惊讶的发现，即一段ADEP保留了抗Mtb的活性，但刺激而不是抑制了ClpXP1P2催化的蛋白质降解。我们的数据进一步表明，该片段稳定了ClpXP1P2复合体，并以不同于完整ADEP的方式与ClpP1P2结合。生物活性片段的构效关系研究确定了药效团，并为开发治疗结核病的新药先导指明了方向。
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.
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影响因子：
4
作者：
Compton, Corey L.;Schmitz, Karl R.;Sauer, Robert T.;Sello, Jason K.
通讯作者：
Sello, Jason K.
影响因子：
3.7
作者：
Dziedzic R;Kiran M;Plocinski P;Ziolkiewicz M;Brzostek A;Moomey M;Vadrevu IS;Dziadek J;Madiraju M;Rajagopalan M
通讯作者：
Rajagopalan M
影响因子：
5.1
作者：
Lavey NP;Coker JA;Ruben EA;Duerfeldt AS
通讯作者：
Duerfeldt AS
影响因子：
3
作者：
Alexopoulos, John A.;Guarne, Alba;Ortega, Joaquin
通讯作者：
Ortega, Joaquin
影响因子：
16.8
作者：
Lee, Byung-Gil;Park, Eun Young;Song, Hyun Kyu
通讯作者：
Song, Hyun Kyu