Discovery And Research Of Novel Antibacterial Agents Related To Folate Synthesis Pathway Protein

Antibacterial drugs are the cornerstone of modern medicine and one of the basic conditions for the improvement of life expectancy.As various antibiotics have been discovered and used in large quantities,bacteria have evolved to develop resistance,and "super bacteria" have become the number one killer of human life and health.The WHO issued a warning that antibiotics will be exhausted,and it is imperative to study new antibiotics.Most of the antibiotics currently marketed are effective against Grampositive bacteria,while the types that are effective against Gram-negative bacteria are decreasing.Gram-negative bacteria are becoming more urgent for new antibiotics.The folate synthesis pathway is conserved in various bacteria,among which there are some target proteins of protein antibiotics,such as the earliest sulfonamides inhibiting the folP protein,and trimethoprim is an inhibitor of folA.Especially on 2017,Iclaprim designed based on the folA structure through clinical phase III experiments has demonstrated that the folate synthesis pathway has important potential in antibiotic research.In this paper,based on the idea of knowledge-designed combination preparations,the folate synthesis pathway protein was studied to solve the problem of shortage of Gram-negative bacteria inhibitors.Compound sulfamethoxazole is an inhibitor of folP protein and folA protein.The minimum inhibitory concentration(MIC)of compound sulfamethoxazole against M.tuberculosis H37 Ra is 41-82 ug/ml,for wild-type M.tuberculosis H37 Ra is 81.92 ug/ml.In Chapter II,Two of the 100 compounds that were virtually screened with the folP protein template were effective against E.coli,seven were effective against M.tuberculosis,and one was effective against both E.coli and M.tuberculosis.The lowest MIC for E.coli was 2 ?g/ml among the 10 compounds,and the lowest MIC for Mycobacterium was 0.125 ?g/ml.In third chapter studies the pabB protein.P-aminobenzenesulfonic acid is one of the raw materials for the synthesis of tetrahydrofolate,and reducing the concentration of p-aminobenzenesulfonic acid helps to increase the susceptibility of bacteria.PabB is one of the important proteins for the synthesis of p-aminobenzoic acid in bacteria.Using the PabB protein in E.coli as a template,95 compounds were screened.It was found that 7 compounds were effective against E.coli,8 compounds were effective against M.tuberculosis H37 Ra,and 3 were effective at the same time.The minimum MIC for E.coli in these 18 compounds was 2 ?g/ml,and the minimum MIC for M.tuberculosis H37 Ra was 0.25 ?g/ml.As the study on folic acid synthesis pathway is deep,The RV3334 protein in Mycobacterium tuberculosis is related to the synthesis of p-aminobenzoic acid.Since RV3334 protein has no crystal structure,genomic analysis RV3334 belongs to the MerR family of transcriptional regulators.According to the structural integrity,50 small molecules were obtained by using the CueR protein in the MerR family of E.coli as a virtual screening protein,and try to purify high purity.