Identification of inhibitors of PvdQ, an enzyme involved in the synthesis of the siderophore pyoverdine.
Identification of inhibitors of PvdQ, an enzyme involved in the synthesis of the siderophore pyoverdine.
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DOI：
10.1021/cb5001586
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发表时间：
2014-07-18
影响因子：
4
通讯作者：
Gulick, Andrew M.
中科院分区：
文献类型：
--
作者：
Wurst, Jacqueline M.;Drake, Eric J.;Theriault, Jimmy R.;Jewett, Ivan T.;VerPlank, Lynn;Perez, Jose R.;Dandapani, Sivaraman;Palmer, Michelle;Moskowitz, Samuel M.;Schreiber, Stuart L.;Munoz, Benito;Gulick, Andrew M.
铜绿假单胞菌产生肽铁载体绿脓菌荧光素，其用于从环境中获取必需的Fe 3+离子。PvdQ是一种Ntn水解酶，是绿脓菌荧光素生物合成所必需的。PvdQ敲除菌株在模型系统中不具有感染性，这表明通过PvdQ抑制来破坏铁载体的产生可以通过防止细胞在大多数生物环境的低铁环境中获得铁而被用作新型抗菌剂的靶标。我们之前描述了一种高通量筛选方法，用于鉴定PvdQ抑制剂，该方法鉴定出的抑制剂的IC50值<100 μM。在这里，我们描述了ML318的发现，PvdQ酰化酶的联芳腈抑制剂。ML318通过结合酰基结合位点抑制PvdQ（IC50 = 20 nM），如结合ML318的PvdQ的X射线晶体结构所证实。此外，PvdQ抑制剂在全细胞测定中是有活性的，防止绿脓菌荧光素产生并限制铜绿假单胞菌在铁限制条件下的生长。
Pseudomonas aeruginosa produces the peptide siderophore pyoverdine, which is used to acquire essential Fe3+ ions from the environment. PvdQ, an Ntn hydrolase, is required for the biosynthesis of pyoverdine. PvdQ knockout strains are not infectious in model systems, suggesting that disruption of siderophore production via PvdQ inhibition could be exploited as a target for novel antibacterial agents, by preventing cells from acquiring iron in the low iron environments of most biological settings. We have previously described a high-throughput screen to identify inhibitors of PvdQ that identified inhibitors with IC50 values of ∼100 μM. Here, we describe the discovery of ML318, a biaryl nitrile inhibitor of PvdQ acylase. ML318 inhibits PvdQ in vitro (IC50 = 20 nM) by binding in the acyl-binding site, as confirmed by the X-ray crystal structure of PvdQ bound to ML318. Additionally, the PvdQ inhibitor is active in a whole cell assay, preventing pyoverdine production and limiting the growth of P. aeruginosa under iron-limiting conditions.
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影响因子：
2.1
作者：
Lehoux, DE;Sanschagrin, F;Levesque, RC
通讯作者：
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影响因子：
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作者：
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DOI：
10.1073/pnas.1222706110
发表时间：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
Kanj, Souha S.;Kanafani, Zeina A.
通讯作者：
Kanafani, Zeina A.
DOI：
10.1073/pnas.0911839107
发表时间：
2010-01-12
影响因子：
11.1
作者：
Bokhove, Marcel;Jimenez, Pol Nadal;Dijkstra, Bauke W.
通讯作者：
Dijkstra, Bauke W.