Study Of The Antibacterial Activity And Action Mechanism Of 2-/4-（P-Dimethylaminostyryl）Quinolinium Derivatives As FtsZ Inhibitors

The discovery of penicillin has saved innumerable lives,making it has been regarded as one of the most important scientific discoveries in the 20^thcentury.Nonetheless,the abuse and misuse of antibiotics shortened the emergence cycle of drug resistance.The emergence of drug-resistant bacteria has made clinical antibiotics lose their potency in treating bacterial infections,so the development of novel antibacterial drugs is urgently needed to solve the antibiotic resistance crisis.The bacterial cell division is essential for bacterial viability as well as growth and reproduction,among which the filamentous temperature sensitive mutant Z（Fts Z）,one of the key proteins required for bacterial cell division,is the first bacterial division protein to reach the division site.The disruption of Fts Z function may cause bacterial death,and it is highly conserved in bacteria,therefore,Fts Z is an ideal target for the development of novel antibacterial drugs.Recent studies have shown that some natural products or synthetic molecules,which contain quinoline or quinazoline scaffold,have better antibacterial activity and are able to target Fts Z proteins,leading to bacterial cell division inhibition.In this thesis,based on the previous research work of our group,two series of 2-/4-（p-dimethylaminostyryl）quinolinium derivatives were designed and synthesized,their antibacterial activities and action mechanism of targeting Fts Z were investigated.The main points of this thesis include:（1）the synthesis of two series of2-/4-（p-dimethylaminostyryl）quinolinium derivatives for structure-activity relationship studies.（2）Antibacterial activity studies found that 2-/4-（p-dimethylaminostyryl）quinolinium derivatives had broad-spectrum antibacterial effect against Gram-positive bacteria,but less effective against Gram-negative bacteria,and the introduction of amine substituent at position 4 of quinolinium ring showed better antibacterial activity than that at position 2.（3）Compounds A3,B3,A2 and A7 showed synergistic effect with methicillin and,it was found that the antibacterial activity of the compounds against Gram-negative bacteria had been enhanced when combining with PMBN.The drug resistance studies proved that these compounds were not readily to induce drug resistance under experimental concentration and had low cytotoxicity and hemolytic toxicity.（4）Compounds A3,B3,A2and A7 can significantly inhibit the bacterial cell division.（5）Compounds A3,B3,A2,and A7 can bind to Fts Z protein with good binding affinity,which causes changes in the secondary structure of Fts Z and promotes Fts Z protein polymerization in a concentration dependent manner but does not affect its GTPase activity.（6）The computational simulation docking indicated that the binding site of the compounds was the hydrophobic interdomain cleft of Fts Z protein,and mainly involved alkyl hydrophobic interactions,amide-pi stacking interactions,carbon-hydrogen bonds,and van der Waals forces.The results showed that 2-/4-（p-dimethylaminostyryl）quinolinium derivatives exhibited significant antibacterial activity against Gram-positive bacteria and interfered with the secondary structure and dynamic polymerization by targeting Fts Z protein,which in turn blocked bacterial division and finally led to bacterial death.Structure-activity relationship analysis found that the introduction of cyclic amine group substituents at position 4 of quinolinium scaffold might be an important research direction.A3 might be a potent Fts Z inhibitor with better antibacterial activity and less toxicity,and was uneasy to induce resistance,which could serve as a lead compound for the development of potential drugs against drug-resistant bacteria and be of value for further research or modification.