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铜绿假单胞菌是一种具有高发病率和死亡率的条件致病菌。以MexAB-OprM外排泵为主的耐药节结化细胞分化家族多药耐药外排系统的存在是铜绿假单胞菌产生多药耐药的主要原因。MexAB-OprM外排泵抑制剂可以显著增强被MexAB-OprM外排的抗生素的活性,作为抗菌药物增效剂,具有良好的临床应用前景。在本研究中,通过小分子库筛选得到了一种新型的MexAB-OprM外排泵抑制剂KL-0153,通过与抗生素的协同活性研究以及EB积累检测证明了其对于MexAB-OprM的抑制活性。在表达MexAB-OprM的铜绿假单胞菌菌株,特别是MexAB-OprM高表达株中,KL-0153与被MexAB-OprM外排的抗生素有协同作用,并且在EB积累检测中,其活性强于阳性药羰基-氰-间-氯苯腙。尽管KL-0153也具有明显的肝肾毒性,但作为先导化合物,对于KL-0153的进一步研究将有助于新型MexAB-OprM外排泵抑制剂的研发。
Pseudomonas aeruginosa is a conditional pathogen with high morbidity and mortality. The main reason for the multidrug resistance of Pseudomonas aeruginosa is the existence of multidrug-resistant efflux system, which is characterized by MexAB-OprM efflux pump-based multi-drug resistant junction cell line. MexAB-OprM efflux pump inhibitor can significantly enhance the activity of antibiotics excreted by MexAB-OprM. As an antimicrobial synergist, MexAB-OprM efflux pump inhibitor has good clinical application prospect. In this study, a novel MexAB-OprM efflux pump inhibitor, KL-0153, was screened by small molecule library and its inhibitory activity against MexAB-OprM was demonstrated by synergistic activity with antibiotics and EB accumulation assay. Among the Pseudomonas aeruginosa strains that express MexAB-OprM, in particular the MexAB-OprM high expression strain, KL-0153 has synergistic effects with the antibiotics that are excreted by MexAB-OprM and is more active in EB accumulation assays than Positive drug carbonyl - cyano - m - chlorophenyl hydrazone. Although KL-0153 also exhibits significant hepatorenal toxicity, as a lead compound, further studies with KL-0153 will facilitate the development of new MexAB-OprM efflux pump inhibitors.