Inhibition of Pseudomonas aeruginosa and Mycobacterium tuberculosis disulfide bond forming enzymes.
Inhibition of Pseudomonas aeruginosa and Mycobacterium tuberculosis disulfide bond forming enzymes.
复制标题
抑制铜绿假单胞菌和结核分枝杆菌二硫键形成酶。
DOI：
10.1111/mmi.14185
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发表时间：
2019
影响因子：
3.6
通讯作者：
P
中科院分区：
文献类型：
--
作者：
Landeta,Cristina;McPartland,Laura;Tran,NgocQ;Meehan,BrianM;Zhang,Yifan;Tanweer,Zaidi;Wakabayashi,Shoko;Rock,Jeremy;Kim,Taehyun;Balasubramanian,Deepak;Audette,Rebecca;Toosky,Melody;Pinkham,Jessica;Rubin,EricJ;Lory,Stephen;P
在细菌中，二硫键使输出到细胞膜或细胞膜外的许多蛋白质具有稳定性，包括细菌毒力因子。因此，参与二硫键形成的蛋白质是开发作为抗生素或抗毒剂的抑制剂的良好靶点，从而导致几种类型的毒力因子同时失活。在这里，我们提出的证据是，二硫键形成酶，DsbB和VKOR，分别是铜绿假单胞菌致病性和结核分枝杆菌生存所必需的。我们还报告了216,767个化合物对P的高温测试结果。铜绿假单胞菌DsbB1和M.利用大肠埃希氏菌细胞进行结核治疗。因为两者都是P。铜绿假单胞菌DsbB1和M.结核是VKOR的补充。基因敲除，我们同时筛选每个互补E的抑制物。表达对二硫键敏感的β半乳糖苷酶的大肠杆菌。从这些筛选中获得的几种抑制剂的性质表明，它们是化学修饰的起点，具有未来抗菌开发的潜力。
In bacteria, disulfide bonds confer stability on many proteins exported to the cell envelope or beyond, including bacterial virulence factors. Thus, proteins involved in disulfide bond formation represent good targets for the development of inhibitors that can act as antibiotics or anti‐virulence agents, resulting in the simultaneous inactivation of several types of virulence factors. Here, we present evidence that the disulfide bond forming enzymes, DsbB and VKOR, are required forPseudomonas aeruginosapathogenicity andMycobacterium tuberculosissurvival respectively. We also report the results of a HTS of 216,767 compounds tested againstP. aeruginosaDsbB1 andM. tuberculosisVKOR usingEscherichia colicells. Since bothP. aeruginosaDsbB1 andM. tuberculosisVKOR complement anE. colidsbBknockout, we screened simultaneously for inhibitors of each complementedE. colistrain expressing a disulfide‐bond sensitiveβ‐galactosidase reported previously. The properties of several inhibitors obtained from these screens suggest they are a starting point for chemical modifications with potential for future antibacterial development.