Antibacterial activity of and resistance to small molecule inhibitors of the ClpP peptidase.
Antibacterial activity of and resistance to small molecule inhibitors of the ClpP peptidase.
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DOI：
10.1021/cb400577b
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发表时间：
2013-12-20
影响因子：
4
通讯作者：
Sello, Jason K.
中科院分区：
文献类型：
--
作者：
Compton, Corey L.;Schmitz, Karl R.;Sauer, Robert T.;Sello, Jason K.
越来越多的证据表明，细菌中的细胞内蛋白水解酶是抗菌药物引人注目的靶点。多份报告表明，人类病原体结核分枝杆菌和其他放线菌可能对小分子特别敏感，这些小分子扰乱了自我分隔的肽酶的活性，这些酶催化细胞内蛋白质的周转，作为ATP依赖的蛋白水解机的组成部分。在这里，我们报道了结构多样的β-内酯的化学合成和评价，这些内酯具有选择性地、自杀地抑制自划分的ClpP多肽酶的特权结构。β--在α-和β-碳上带有某些取代基的内酯被发现对结核分枝杆菌有毒性。利用亲和标记的生物活性β-内酯类似物，在一系列化学蛋白质组学实验中，我们选择性地从两种与结核分枝杆菌相关的不同放线杆菌的活培养物中捕获了ClpP1P2多肽酶。重要的是，我们发现抑制生长的β-内酯在体外也通过在ClpP2催化丝氨酸上形成共价加合物来灭活结核分枝杆菌ClpP1P2多肽酶。鉴于这些化合物的强大抗菌活性和它们的药用潜力，我们试图确定固有的耐药机制。利用基因组挖掘策略，我们在天蓝色链霉菌中鉴定了β内酯耐药性的遗传决定因素，天蓝色链霉菌是结核分枝杆菌的非致病亲缘关系。总之，这些发现验证了ClpP抑制作为抗菌药物开发策略的潜力，并定义了细菌抵抗ClpP抑制剂毒性作用的机制。
There is rapidly mounting evidence that intracellular proteases in bacteria are compelling targets for antibacterial drugs. Multiple reports suggest that the human pathogen Mycobacterium tuberculosis and other actinobacteria may be particularly sensitive to small molecules that perturb the activities of self-compartmentalized peptidases, which catalyze intracellular protein turnover as components of ATP-dependent proteolytic machines. Here, we report chemical syntheses and evaluations of structurally diverse β-lactones, which have a privileged structure for selective, suicide inhibition of the self-compartmentalized ClpP peptidase. β-lactones with certain substituents on the α- and β-carbons were found to be toxic to M. tuberculosis. Using an affinity-labeled analog of a bioactive β-lactone in a series of chemical proteomic experiments, we selectively captured the ClpP1P2 peptidase from live cultures of two different actinobacteria that are related to M. tuberculosis. Importantly, we found that the growth inhibitory β-lactones also inactivate the M. tuberculosis ClpP1P2 peptidase in vitro via formation of a covalent adduct at the ClpP2 catalytic serine. Given the potent antibacterial activity of these compounds and their medicinal potential, we sought to identify innate mechanisms of resistance. Using a genome mining strategy, we identified a genetic determinant of β-lactone resistance in Streptomyces coelicolor, a non-pathogenic relative of M. tuberculosis. Collectively, these findings validate the potential of ClpP inhibition as a strategy in antibacterial drug development and define a mechanism by which bacteria could resist the toxic effects of ClpP inhibitors.
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DOI：
10.1016/j.bbamcr.2011.06.007
发表时间：
2012-01
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Baker TA;Sauer RT
通讯作者：
Sauer RT
影响因子：
5.6
作者：
Lee, Mary E.;Baker, Tania A.;Sauer, Robert T.
通讯作者：
Sauer, Robert T.
影响因子：
10.5
作者：
Gottesman, S;Roche, E;Sauer, RT
通讯作者：
Sauer, RT
影响因子：
56.9
作者：
Darwin, KH;Ehrt, S;Nathan, CF
通讯作者：
Nathan, CF
影响因子：
3.2
作者：
MAURER, KH;PFEIFFER, F;MECKE, D
通讯作者：
MECKE, D