取代苯胍衍生物逆转多黏菌素耐药性的作用机制研究

细菌耐药性已经成为全球性的医学难题，尤其是革兰氏阴性菌的多重耐药性问题最为突出。多黏菌素作为治疗多重耐药革兰氏阴性菌引起严重感染的最后一道防线，近年来耐药现象非常严重，尤其是去年发现mcr-1多黏菌素耐药基因可介导耐药性的水平传播，导致临床几乎无药可用。我们的初步研究发现取代苯胍衍生物不仅可以逆转多黏菌素耐药大肠杆菌的耐药性，还对多粘菌素敏感菌具有协同增效作用。本申请课题是国内外首次将取代苯胍衍生物作为多黏菌素耐药性逆转剂，旨在从中筛选出对质粒和染色体介导多黏菌素耐药大肠杆菌具有最佳逆转效果的化合物，且证实其在体内对多黏菌素耐药有良好的逆转活性和安全性，然后从耐药质粒消除、外排泵的表达、二元调控系统的调节和类脂A修饰等方面研究其对多黏菌素耐药性逆转的可能作用机制，从而更好地了解多黏菌素耐药机制的产生，为多黏菌素耐药逆转剂的研发和减缓多黏菌素耐药性的产生提供实验和理论依据。

In this century, bacterial resistance to antibiotics has become a global medical problem, especially multidrug-resistant Gram-negative bacteria. Polymyxin is the last treatment option for severe infections caused by multidrug resistant Gram-negative bacteria. However, in recent years, polymyxin resistance has become increasingly serious, especially the emergence of the first plasmid-mediated transferable polymyxin resistance gene mcr-1, which was identified in China last year and soon detected among many other countries, has resulted in almost no treatment options available in clinic. Our previous study showed that substituted phenyl guanidine derivatives could not only reverse the drug resistance of polymyxin-resistant Escherichia coli, but also showed a synergistic effect on polymyxin-susceptible bacteria. In this study, substituted phenyl guanidine derivatives are firstly investigated as polymyxin resistance reversal agents, aimed at screening best compound with excellent activity to reverse polymyxin resistance in vitro, great activity and safety in vivo as well. Then the possible mechanism of this compound to reverse polymyxin resistance will be investigated through plasmid elimination, efflux pump expression, regulation of two-component system, modification of lipid A, ion and pH changes, in order to better understand polymyxin resistance mechanisms, and provide experimental and theoretical basis for the development of polymyxin reversal agent and control of polymyxin resistance.