Exploring the inhibition of the soluble lytic transglycosylase Cj0843c of Campylobacter jejuni via targeting different sites with different scaffolds.
Exploring the inhibition of the soluble lytic transglycosylase Cj0843c of Campylobacter jejuni via targeting different sites with different scaffolds.
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DOI：
10.1002/pro.4683
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发表时间：
2023-07
期刊：
影响因子：
--
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中科院分区：
文献类型：
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细菌裂解糖基转移酶(LTS)有助于肽聚糖的细胞壁代谢，是增强β-内酰胺类抗生素以克服抗生素耐药性的潜在药物靶点。由于LT抑制剂的开发还没有得到充分的探索，我们以结构导向的方式探索了15个N-乙酰基杂环化合物对空肠弯曲菌LT Cj0843c的抑制和结合能力。合成了10个具有C1位取代的GlcNAc类似物，其中两个在C4或C6位有额外的修饰。大部分化合物对Cj0843c活性有微弱的抑制作用。C4位改变的化合物，用a-NH2取代-OH，C6位加a-CH3，产生更好的抑制效果。所有10个GlcNAc类似物通过Cj0843c晶体的浸泡实验进行了结晶学分析，发现它们都与+1+2糖亚基结合，其中一个还与−2−1亚基区结合。我们还探索了其他含N-乙酰基的杂环，发现唾液酸酶抑制剂N-乙酰基-2，3-脱氢-2-脱氧神经氨酸和西司他丁B对Cj0843c有微弱的抑制作用，并且结晶学上与−2−1亚基结合。前者的类似物也表现出抑制和晶体结合，包括扎那米韦胺。后一组杂环将它们的N-乙酰基定位在−2亚基上，并在−1亚基上相互作用。总体而言，这些结果可能通过探索不同的亚基和新的支架为LT抑制提供新的机会。这些结果也增加了我们对Cj0843c关于肽聚糖GlcNAc亚位结合偏好和对催化E390质子化状态的配体依赖的调节的机制的理解。
Bacterial lytic transglycosylases (LTs) contribute to peptidoglycan cell wall metabolism and are potential drug targets to potentiate β‐lactam antibiotics to overcome antibiotic resistance. Since LT inhibitor development is underexplored, we probed 15 N‐acetyl‐containing heterocycles in a structure‐guided fashion for their ability to inhibit and bind to the Campylobacter jejuni LT Cj0843c. Ten GlcNAc analogs were synthesized with substitutions at the C1 position, with two having an additional modification at the C4 or C6 position. Most of the compounds showed weak inhibition of Cj0843c activity. Compounds with alterations at the C4 position, replacing the ‐OH with a ‐NH2, and C6 position, the addition of a ‐CH3, yielded improved inhibitory efficacy. All 10 GlcNAc analogs were crystallographically analyzed via soaking experiments using Cj0843c crystals and found to bind to the +1 +2 saccharide subsites with one of them additionally binding to the −2 −1 subsite region. We also probed other N‐acetyl‐containing heterocycles and found that sialidase inhibitors N‐acetyl‐2,3‐dehydro‐2‐deoxyneuraminic acid and siastatin B inhibited Cj0843c weakly and crystallographically bound to the −2 −1 subsites. Analogs of the former also showed inhibition and crystallographic binding and included zanamivir amine. This latter set of heterocycles positioned their N‐acetyl group in the −2 subsite with additional moieties interacting in the −1 subsite. Overall, these results could provide novel opportunities for LT inhibition via exploring different subsites and novel scaffolds. The results also increased our mechanistic understanding of Cj0843c regarding peptidoglycan GlcNAc subsite binding preferences and ligand‐dependent modulation of the protonation state of the catalytic E390.
影响因子：
3.7
作者：
Vijayaraghavan J;Kumar V;Krishnan NP;Kaufhold RT;Zeng X;Lin J;van den Akker F
通讯作者：
van den Akker F
影响因子：
4.8
作者：
Kim, Choon;Tomoshige, Shusuke;Lee, Mijoon;Zgurskaya, Helen I.;Mobashery, Shahriar
通讯作者：
Mobashery, Shahriar