Expand The Bioactive Chemical Space Of Bacterial FabF-specific Inhibitors Via Manipulation Of Anthrabenzoxocinones Biosynthetic Pathways

Aromatic polyketide compounds are important categories in big family of bioactive natural products,whose members include widely used clinical antimicrobial agents tetracycline,antitumor drugs daunorubicin and the mithramycin,etc.The biosynthesis of aromatic polyketide compounds is catalyzed by polyketone synthetase(PKS)system,although according to the different catalytic mechanism,aromatic polyketone compounds can be subdivided into I,?,?I.Anthrabenzoxocinones(ABXs)are a small group of type ? aromatic polyketide compounds,but most of them are the type ? polyketone.Aromatic ring skeleton formed by the conservative enzymology mechanism makes a huge number of the type ? polyketone compounds,but most of them are the type ? polyketone.formed by a class of novel ARO enzymes specifically to cyclize discrete conjugate benzene ring skeleton;2)catalyzed by a class of new KR and CYC enzymes to form chiral ketal oxygen bridge skeleton.10-dimethylanthrone unit can tightly target the condensation enzyme FabF of bacterial FASs.To reform the carbon skeleton modification after gene,expand the diversity of the new compounds,screening,toxicity with stronger get lower antibacterial lead compounds.Because the structure of ABX is very complex,it is difficult to obtain a new structure similar via the traditional chemical modification method,In this work,we from the perspective of biosynthesis of modification by parsing and modified related genes,in order to obtain efficiently a series of new structural analogues is used for the screening of active research,Early on,we obtained the biosynthesis pathway of ABX with the method of gene cloning,and then analyzed the genetic function of it.Fatty acid synthase,mainly exists in bacteria,different from the higher biological FAS I fatty acid synthase,Fatty acids are important components of the cell membrane,also is the important energy storage material,FabF is key enyme of type ? fatty acid biosynthesis for long chain extend,1,3-dihydroxy-10,10-dimethylanthrone unit that can tightly target the condensation enzyme FabF of bacterial FASs.We found that there are three methyltransferase and two related halide enzyme genes in the(-)-ABX biosynthetic pathway.abxH is a halogenase and abxN is a methyltrasferases by the knockout experiments in vivo gene clusterd and heterologous expression.the protein expression in vitro study also confirmed the abxH and abxN activity.Because of chloride to replace ABX can strong antibacterial activity,by building the carrier,Takeing halogenase genes into to a lack of halogenated enzyme production(-)+ABX Streptomyces.Sp.FXJ1.264 strains.The knockout,covering fermentation and in vitro catalytic synthesis.A total of 14 kinds of new ABX analogues was found.Through the determination of MIC values,show that they are active better inhibitor.To sum up,we put new structure,active ABX type ? polyketone compounds as the research object,Use the method of combinatorial biosynthesis and biotransformation for 1,3-dihydroxy-10,10-dimethylanthrone unit FAS ? inhibitors analogues On discovering new antibiotics has practical guidance,greatly enrich polyketone structure diversification of means and structure types,for polyketone drug research and development have a positive role.