The Study Of 9,10-dihydroacridine Derivatives As Antimicrobial Agents Targeting FtsZ

Antibiotics are effective drugs against bacterial pathogens,but with the emergence and spread of "super bacteria" in the world,the efficacy of antibiotics is affected.Therefore,emergency action is needed to develop a new generation of antibiotics to help solve this increasingly serious public health issue.9-aminoacridine has been used as an antimicrobial and antimalarial drug since the early20 th century.Subsequently,3,6-diaminoacridine was found to be effective in inhibiting tumor growth in animal models.Therefore,acridine derivatives have rich biological activity and are potential small molecule skeletons in drug discovery field.In this study,a class of 9,10-dihydroacridine derivatives B1-B4 was screened and found to have stronger antibacterial effect than the reported 9-acridine derivatives.On the other hand,methicillin-resistant Staphylococcus aureus,vancomycin-resistant Staphylococcus aureus,ancomycin-resistant Enterococcus faecalis,methecillin-resistance Staphylococcus epidermidis and other drug-resistant strains had good antibacterial effects,with a minimum MIC of 0.125μg/m L(0.26 μM).Under the action of the compound,the morphology of the bacteria was significantly prolonged,so it was speculated that the antibacterial mechanism was related to the FtsZ protein.FtsZ,namely filamentous temperature-sensitive protein Z,is the first functional protein found to be related to bacterial cell division.Due to its highly conserved nature and importance,FtsZ is considered to be an ideal target in the search for novel antimicrobial agents.In the process of cell division,FtsZ calls other dividing proteins in the center of the cell to act together,form the Z ring,and contract the Z ring to achieve cell division.In this study,through the study of the interaction between the compound and FtsZ protein,it was found that the compound disrupted the dynamic polymerization of FtsZ protein and inhibited its hydrolytic activity as GTP-enzyme.In summary,this study found that 9,10-dihydroacridine derivatives have good antimicrobial activity against drug-resistant bacteria.The structure-activity relationship analysis showed that the introduction of p-methylbenzene ring and N-xanthene at site 10 not only improved the antimicrobial activity,but also showed better interference effect with FtsZ.In addition,9,10-dihydroacridine derivatives have excellent synergistic effect with methicillin,which brings more possibilities for the development of this compound.