Structure-based inhibitor design for reshaping bacterial morphology.
Structure-based inhibitor design for reshaping bacterial morphology.
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DOI：
10.1038/s42003-022-03355-3
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发表时间：
2022-04-28
影响因子：
5.9
通讯作者：
中科院分区：
文献类型：
--
作者：
肠道病原菌空肠弯曲杆菌的螺旋形态对肠粘膜上皮细胞的侵袭至关重要。鉴于这种细胞形态在空肠弯曲菌感染的病理中起作用，通过药物干预对其进行重组可能是一种尚未探索的预防感染的手段。我们最近报道了肽聚糖水解酶3(Pgp3)参与了空肠弯曲菌螺旋形的形成。在此，我们报道了以Pgp3为靶点的羟甲酸基抑制剂的设计和合成。空肠弯曲菌细胞暴露于这些抑制剂后，形态由螺旋状变为杆状，与Pgp3缺失突变体的情况类似。Pgp3与抑制剂形成的络合物的晶体结构提供了作用机理的证据，揭示了抑制剂在活性部位的结合模式，并得到了动力学和分子动力学模拟的支持。暴露在这些抑制剂下的空肠弯曲杆菌经历了从螺旋形细菌到杆状细菌的形态变化，这一事件降低了宿主细胞的入侵能力。这一概念的证明表明，形态的改变会影响对细菌感染的干扰。肽聚糖水解酶3(Pgp3)抑制剂可以改变空肠弯曲菌的螺旋形态，使其变为杆状，降低其毒力。
The spiral shape of intestinal pathogen Campylobacter jejuni is critical for invasion of intestinal mucosa epithelial cells. Insofar as this cell morphology plays a role in the pathology of C. jejuni infection, its restructuring by pharmacological intervention could be an unexplored means to prevention of infection. We recently described that peptidoglycan hydrolase 3 (Pgp3) is involved in the spiral-shape formation of C. jejuni. We report herein the design and synthesis of the hydroxamate-based inhibitors targeting Pgp3. C. jejuni cells exposed to these inhibitors changed from the helical- to rod-shaped morphology, comparable to the case of the pgp3-deletion mutant. Evidence for the mechanism of action was provided by crystal structures of Pgp3 in complex with inhibitors, shedding light into the binding modes of inhibitors within the active site, supported by kinetics and molecular-dynamics simulations. C. jejuni exposed to these inhibitors underwent the morphological change from helical- to rod-shaped bacteria, an event that reduce the ability for invasion of the host cells. This proof of concept suggests that alteration of morphology affects the interference with the bacterial infection. Peptidoglycan hydrolase 3 (Pgp3) inhibitors are designed that can change the helical morphology of Campylobacter jejuni to rod-shaped and decrease its virulence.
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影响因子：
5.5
作者：
Goetz, Andreas W.;Williamson, Mark J.;Xu, Dong;Poole, Duncan;Le Grand, Scott;Walker, Ross C.
通讯作者：
Walker, Ross C.
影响因子：
6.7
作者：
Frirdich E;Biboy J;Adams C;Lee J;Ellermeier J;Gielda LD;Dirita VJ;Girardin SE;Vollmer W;Gaynor EC
通讯作者：
Gaynor EC
影响因子：
2.8
作者：
Mattheus, Wesley;Botteldoorn, Nadine;Dierick, Katelijne
通讯作者：
Dierick, Katelijne
影响因子：
15
作者：
Mahasenan KV;Molina R;Bouley R;Batuecas MT;Fisher JF;Hermoso JA;Chang M;Mobashery S
通讯作者：
Mobashery S
DOI：
10.1107/s0907444909042073
发表时间：
2010-01
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Chen VB;Arendall WB 3rd;Headd JJ;Keedy DA;Immormino RM;Kapral GJ;Murray LW;Richardson JS;Richardson DC
通讯作者：
Richardson DC