Antibacterial Activity Evaluation And Action Mode Study Of FtsZ Inhibitor Thiazole Orange Derivatives

The emergence of antibiotics has provided an important guarantee for human health.However,unplanned abuse of antibiotics had led to bacterial resistance problems in recent decades.Many traditional antibiotics had lost their effectiveness,and bacterial infections had become one of the major health problems worldwide.The increasing incidence of multi-drug resistant bacterial infections has made it imperative to develop new antibacterial drugs.Filamenting temperature sensitive mutant Z(Fts Z)had become an attractive target for the development of new antibiotics due to its high conservation,functional importance and structural similarity in bacteria.In recent years,researchers had found that compounds with benzothiazole or quinoline scaffolds are expected to be novel Fts Z inhibitors.Members of our research group synthesized a series of thiazole orange derivatives(24 compounds),and studied the antibacterial activity and mechanism of these derivatives.The main contents of this thesis include:(1)It had been found that thiazole orange derivatives have a broad-spectrum antibacterial effect against Gram-positive and Gram-negative bacteria through the antibacterial activity in vitro.The compounds could simultaneously inhibit the growth of Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus(MRSA),vancomycin-resistant Enterococcus(VRE)and and some Gram-negative bacteria such as NDM-1 Escherichia coli.(2)Through bacterial morphology studies,it could be found that compounds 4a-4b could prevent bacterial division and prolong the bacteria without destroying the bacterial cell membrane structure,which leads to bacterial cell death.(3)Compounds 4a1、4a4、4b1 and 4b4 had synergistic or partial synergistic effects with methicillin and vancomycin.Drug resistance studies have found that these compounds were not easy to cause bacterial resistance mutations,and 4a4 and 4b4 had lower cytotoxicity.(4)Compounds 4a-4b could disrupt the formation of Z-ring in bacteria,and 4a4 and 4b4 promote the polymerization of Fts Z protein in a dose-dependent manner in vitro without interfering with GTPase activity.(5)In the docking simulation of compound-protein molecules,compounds could interact with Fts Z proteins through carbonhydrogen bonds and could also generate electrostatic interactions and hydrophobic interactions with amino acid residues.The results showed that the thiazole orange derivatives in this study had good and broadspectrum antibacterial activity,and 4a-4b could stimulate Fts Z polymerization by targeting Fts Z and disturb the dynamic assembly of Z-ring formation to show antibacterial activity,which had certain advantages in the development of antibacterial drugs.The structure-activity relationship analysis showed that the amino terminal group of the benzothiazole fragment and the small substituent at the 2-position of the quinoline were important in conferring strong antibacterial activity to the thiazole orange derivative.