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随着多药耐药和广泛耐药结核的迅速蔓延,迫切需要寻求对抗结核的新手段。结核分枝杆菌对β-内酰胺类抗菌药物的固有耐药性限制了β-内酰胺类抗菌药物在结核治疗上的应用,而A类(Ambler分类)β-内酰胺酶BlaC的表达是结核分枝杆菌对β-内酰胺类抗菌药物耐药的最主要原因。抑制BlaC可以恢复结核分枝杆菌对于β-内酰胺类抗菌药物的敏感性,因此BlaC抑制剂可能成为新型的抗结核药物增效剂,并成为治疗结核的新途径。在本研究中,表达并纯化了结核分枝杆菌BlaC,并以此为基础构建了BlaC抑制剂的筛选模型,通过条件优化使该模型适用于高通量筛选。通过对26 400个化合物样品的筛选,得到了22个BlaC抑制剂,阳性率为0.083%。这一研究为可用于临床的新型抗结核药物增效剂的发现奠定了基础。
With the rapid spread of multidrug-resistant and drug-resistant tuberculosis, there is an urgent need to find new ways to combat tuberculosis. The inherent resistance of M. tuberculosis to β-lactam antibiotics limits the use of β-lactam antibiotics in the treatment of tuberculosis, whereas the expression of class A (Ambler classification) β-lactamase BlaC is tuberculosis Mycobacterium β-lactam antibiotic resistance of the most important reason. Inhibition of BlaC can restore the susceptibility of M. tuberculosis to beta-lactam antibiotics, so that a BlaC inhibitor may become a new antituberculosis drug synergist and a new way to treat tuberculosis. In this study, Mycobacterium tuberculosis BlaC was expressed and purified, and based on which BlaC inhibitor screening model was constructed. The model was optimized for high-throughput screening by conditional optimization. Twenty-two BlaC inhibitors were obtained by screening 26,400 compounds with a positive rate of 0.083%. This study lays the foundation for the discovery of new antituberculosis drug potentiators that are clinically useful.