Study On The Anti Drug-Resistant Bacteria Activity About Compounds From Three Strains Of Microorganism And Two Kinds Of Medicinal Plants

The discovery of antibiotics is regarded as one of the most important breakthroughs in modern medicine.However,with the wide use of antibiotics,some Gram-positive bacteria strains such as methicillin-resistant Staphylococcus aureus,penicillin resistant Streptococcus pneumoniae,vancomycin resistant Enterococcus,Pseudomonas aeruginosa and other bacteria began to appear multidrug resistance,even extremely high drug resistance and complete resistance,which caused serious difficulties in clinical treatment.With the spread of highly drugresistant strains,the treatment of severe infectious diseases becomes more complicated.The improvement of drug resistance reduces the effect of antibiotics,resulting in the increase of morbidity,mortality and medical costs.The appearance of drug resistance bacterial has brought great challenges to clinical anti infection treatment.The infection of drug-resistant bacteria has become the main threat in the field of public health.Therefore,the research of antimicrobial agents has shifted from common bacteria to drug-resistant bacteria,and the development of new active drugs against drug-resistant bacteria is imminent.Medicinal plants and fungi in wild environment can produce a variety of metabolites with unique biological activity,but few reports on their activities against drug-resistant bacteria were reported.In this paper,constituents from nature resources such as Chaetomium sp.,Penicillium sp.,Stephania sinica Diels and Solanum alatum Moench were studied,their drug-resistant bacteria activity were also screened:Twenty eight compounds(MA-1~ MA-28)were isolated from C.olivaceum SD-80 a with the help of gene mining technology for the first time.Among them,4 naphthenic polyketides containing tamaric acid group,Chaetolivacines A(MA-1),Myceliothermophin E(MA-2),Chaetolivacines B(MA-3),Chaetolivacines C(MA-4)were isolated from C.olivaceum SD-80 A by using DAases(Myc B)as biomarkers for biosynthesis,Chaetolivacines A-C are three new compounds.In the structural analysis of the new compounds,we found that the end of the tamaric acid group in compounds MA-1,MA-3 and MA-4 is benzene ring.Compounds MA-3and MA-4 are chiral isomers of C-21 with different spatial configurations.Compounds MA-1~MA-4 were tested against drug-resistant bacteria.Compounds MA-2 and MA-3 had good inhibitory effect on MRSA with MIC values of 15.8 and 27.1 ?m,respectively.The MIC inhibitory values of 21R-MA-3 on SA and MRSA were 10.8 and 27.1 ? m,respectively,while the MIC values of 21S-MA-4 on SA and MRSA were not clearly reflected(> 100 ?m),indicating that the configuration difference of C-21 played an important role in the anti MRSA activity in these two compounds.The biosynthesis pathway of compounds MA-1~MA-4 was proposed for the first time,which provided a theoretical basis for the biosynthesis of these compounds in Chaetomium sp..One new compound,Isoviridicatol(MB-4),including eight known compounds(MB-1~MB-3,MB-5~MB-9)were isolated from C.convolutum SD.84 for the first time.In the structural analysis of the new compound MB-4 was found as a isomer of MB-3.The results of drug-resistant bacteria activity showed that compounds MB-1~MB-3 and MB-5~MB-7 had weak inhibitory activities against SC5314,17#,G5 and PA14,but had good inhibitory activities against SA and MRSA.Among them,compounds MB-1 and MB-3 had strong SA inhibitory activity with MIC values of 11.2 and 12.4 ?m,respectively.In the data of MRSA inhibitory activity,MB-2 showed good inhibitory activity with MIC value of 13.2 ?m;MB-2 showed moderate anti SA activity,MIC was 26.4 ?M.compounds MA-2 and MA-3 had strong inhibitory effect on MRSA.Through the activity test,we can infer that the same type of compounds isolated from C.convolutum SD.84 have good anti drug resistance activity for SA and MRSA.However MB-4 did not show any activity against any bacteria after the detection of drug-resistant bacteria.It can be inferred that MB-3 has strong inhibitory activity,but MB-4 has no activity due to the different space configuration caused by isomerism.One new compound,Isopaxilline(MC-14),together with 16 known compounds(MC-1~MC-13,MC-15~MC-17)were isolated from P.paxilli SD.40-2 for the first time.Based on OSMAC method,three groups of P.paxilli SD.40-2 were cultured in the non supplemented medium(null),azacytidine medium(N)and nicotinamide medium(Y).One new compound,MCN-3,along with 6 know compounds(MCN-1~MCN-2,MCN-4~MCN-7)were isolated from P.paxilli SD.40-2(N)for the first time.This experiment verified the application of OSMAC method in P.paxilli sd.40-2.New secondary metabolites could be obtained from sea cucumber endophyte P.paxilli SD.40-2 by adjusting the medium state and opening the silencing gene signal using inhibitors.Modern medical-pharmaceutical screening and pharmacology showed that Solanaceae Solanum and Menispermaceae Stephania plants can produce antibacterial active components,Solanaceae Solanum and Stephania of Stephania are rich in active ingredients.The crude extracts of petroleum ether,ethyl acetate and n-butyl were obtained from the dried root tubers of Stephania Sinica Diels.The activity evaluation table of crude extracts showed that Et OAc crude extracts showed activity against many pathogens.Seven compounds(MD-1~MD-7)were isolated from the ethyl acetate extract of Stephania Sinica Diels for the first time.The results of antimicrobial screening of compound MD-1 showed that MD-1 had certain inhibitory activity on SA and MRSA with MIC values of 40.7 and 10.2 ?m,respectively.In the cytotoxicity test,MD-1 had certain cytotoxicity against MGC-803,NCI-H460,SKOV3 and T24.Among them,MD-1had good cytotoxicity against MGC-803 and T24,with IC50 values of 21.84 and 21.84 ?m,respectively.Hydroxycamptothecin was the positive control.Thirteen compounds(MF-1~MF-13)were isolated from the ethyl acetate crude extract of Solanum alatum Moench for the first time.The activities of some compounds against drugresistant bacteria were evaluated.The results showed that the compounds exhibited weak inhibitory activities against SC5314,17 #,G5 and PA14.MF-2 and MF-10 showed moderate activities against SA and MRSA.The MIC values of MF-2 were 68.8 ?m(SA)and 68.8 ?m(MRSA),respectively,and the MIC values of MF-10 were 72.5 ?m(SA)and 72.5 ?m(MRSA),respectively.In this paper,we systematically isolated five systems of natural microorganisms and medicinal plants and obtained eighty one compounds.Among them,six new compounds were found,including three naphthenic polyketones containing telamic acid group,one penicillin alcohol compound and two paxilline compounds.It is the first time to evaluate the activity of the isolated compounds against drug-resistant bacteria,which brings new hope for the treatment of new drug-resistant drugs and drug-leading compounds,especially for the treatment of methicillin-resistant Staphylococcus aureus,Pseudomonas aeruginosa and vancomycin resistant Enterococcus.For the first time,gene sequencing of specific strains was used to find the target active products,and OSMAC method was used to control the microbial metabolites to find new active metabolites,which provided a theoretical basis for the exploration of microbial active metabolites in different ways,and opened up a new way for the research of new drug active monomers.