Department of Chemistry, University of Bath, Bath, BA2 7AY, UK.
School of Physical Sciences, University of Kent, Canterbury, CT2 7NH, UK.
Sci Rep. 2021 Feb 12;11(1):3726. doi: 10.1038/s41598-021-83257-2.
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.
由于留置导尿管的感染和堵塞发生率高，且后果严重，因此需要对此加以关注。细菌酶可作为小分子干预人类细菌感染的靶点。脲酶是一种金属酶，已知其在与导管相关的奇异变形杆菌感染的发病机制和毒力中起关键作用。将脲酶作为治疗候选物，可在不影响细菌适应性的情况下削弱细菌毒力，从而限制对入侵种群的选择性压力，并降低其获得耐药性的速度。我们描述了小分子酶抑制剂 2-巯基乙酰胺（2-MA）的设计、合成和体外评估，该抑制剂可在生理相关的留置导尿管尿路模型中防止结石形成和堵塞。2-MA 是尿素的结构类似物，对脲酶显示出有前景的竞争性活性。计算机对接实验证明了 2-MA 的竞争性抑制作用，而进一步的量子水平建模表明了两种可能的结合机制。
