NDM-1抑制剂的设计、合成及作用机制

Spread of multidrug-resistant in animal agriculture usually decrease even inactive the effective of antibacterial drugs in the market. Despite this, spread of multidrug-resistant in animal agriculture not only causes economic losses in animal husbandry livestock farming, but also threats the safety of animal derived food. The New Delhi metallo-β-lactamase-1 (NDM-1) has been found to be one of the main factor to confer multidrug-resistant bacterials. Unfortunately, treatment options for NDM-1 producers are very limited. Development and research of NDM-1 inhibitors is very important to control the resistance of animal derived resistant bacterials and extend the life of antibacterial drugs in the market. For captopril could enhance the antibacterial activity of imipenem against the bacterial with NDM-1, according to the structure of the X-ray structure of NDM-1 active site in complex with captopril, we assumed that this active site might be the target of these derivatives..In this project, based on the binding site of captopril and NDM-1, captopril is considered as lead compound as well as NDM-1 is considered as target, series of captopril derivatives will be designed and synthesised. The activities, which enhancement sensitive of resistant bacterial with NDM-1, of these captopril derivatives will be evaluated in vitro and in vivo. Investigation of the structure-activity relationship and modification of these derivatives will also be carried out. Then we hope these work could yield a new drug for animal use or a new lead compound which could enhance the sensitive of resistant bacterial with NDM-1. The mechanism of the NDM-1 inhibitor will also be clarified.

多重耐药菌在兽医临床的流行，导致常用抗菌药疗效下降甚至无效，不仅给畜牧养殖业造成重大损失，也严重威胁动物源性食品安全，甚至对人类健康产生重大影响。NDM-1酶是导致细菌多重耐药的主要原因之一，但能用于防控产NDM-1耐药菌的药物十分匮乏。研制开发NDM-1抑制剂，对控制NDM-1引起的动物源耐药菌耐药性、延长现有抗菌药物使用寿命具有重要意义。基于卡托普利具有增强产NDM-1耐药菌对亚胺培南敏感性的作用，根据其与NDM-1共结晶的结构，我们推测NDM-1酶与卡托普利结合处的活性空腔可能是该类衍生物发挥作用的靶点。.本项目拟以NDM-1酶为作用靶标，针对NDM-1活性空腔的氨基酸残基，保留卡托普利分子中与NDM-1有强相互作用的的巯基、酰氨氧及羧基氧三个活性基团，在分子结构中引入富电子基团，设计并合成系列卡托普利衍生物，评价衍生物体内外增强产NDM-1耐药菌敏感性的活性，基于衍生物的构效关系，

本项目以NDM-1酶为靶点，以卡托普利为先导化合物，设计合成了系列具有硫代乙酰基结构的化合物，初步阐明了所合成化合物增强产NDM-1酶耐药菌敏感性的作用机制源于该类化合物与NDM-1酶的结合。该类化合物通过与NDM-1酶中的锌离子、GLN-123、LYS-211等氨基酸残基结合，抑制NDM-1酶水解亚胺培南的活性；对衍生物抑酶作用机制的进一步研究发现，衍生物分子通过与锌离子结合，替换原NDM-1酶中用于水解亚胺培南的水分子，抑制NDM-1酶对亚胺培南的水解，进而增强产NDM-1酶耐药菌对亚胺培南的敏感性，尤其该类化合物分子中的硫原子能显著增强化合物与NDM-1酶中锌离子的结合，此外酰基氧、硫原子侧引入的芳香环也能增强化合物与NDM-1酶的相互作用。本项目研究成果可为动物专用耐药菌抗菌增效剂的设计、开发提供理论依据。