A small-molecular inhibitor against Proteus mirabilis urease to treat catheter-associated urinary tract infections.
A small-molecular inhibitor against Proteus mirabilis urease to treat catheter-associated urinary tract infections.
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DOI：
10.1038/s41598-021-83257-2
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发表时间：
2021-02-12
影响因子：
4.6
通讯作者：
Jenkins ATA
中科院分区：
文献类型：
--
作者：
Milo S;Heylen RA;Glancy J;Williams GT;Patenall BL;Hathaway HJ;Thet NT;Allinson SL;Laabei M;Jenkins ATA
留置导尿管感染和堵塞的发生率高，危害严重。细菌酶被用作小分子干预人类细菌感染的靶标。尿素酶是一种金属酶，已知在导管相关奇异变形杆菌感染的发病机制和毒力中起关键作用。靶向脲酶作为治疗候选物有助于解除细菌毒力而不影响细菌适应性，从而限制施加在入侵种群上的选择性压力并降低其获得抗性的速率。我们描述了小分子酶抑制剂2-巯基乙酰胺（2-MA）的设计，合成和体外评价，它可以防止在体外模型的导尿管在生理上有代表性的结垢和堵塞。2-MA是尿素的结构类似物，显示出对尿素酶的有希望的竞争活性。在计算机对接实验表明2-MA的竞争性抑制，而进一步的量子水平建模表明两种可能的结合机制。
Infection and blockage of indwelling urinary catheters is significant owing to its high incidence rate and severe medical consequences. Bacterial enzymes are employed as targets for small molecular intervention in human bacterial infections. Urease is a metalloenzyme known to play a crucial role in the pathogenesis and virulence of catheter-associated Proteus mirabilis infection. Targeting urease as a therapeutic candidate facilitates the disarming of bacterial virulence without affecting bacterial fitness, thereby limiting the selective pressure placed on the invading population and lowering the rate at which it will acquire resistance. We describe the design, synthesis, and in vitro evaluation of the small molecular enzyme inhibitor 2-mercaptoacetamide (2-MA), which can prevent encrustation and blockage of urinary catheters in a physiologically representative in vitro model of the catheterized urinary tract. 2-MA is a structural analogue of urea, showing promising competitive activity against urease. In silico docking experiments demonstrated 2-MA’s competitive inhibition, whilst further quantum level modelling suggests two possible binding mechanisms.
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