Anti-MSM Activity Screening Of Natural Products And Study On The Secondary Metabolites Of Several Active Strains

Tuberculosis(TB)is a deadly infectious disease caused by mycobacterium tuberculosis infection.The drug discovery of streptomycin,isoniazid and rifampicin from natural products has provided a variety of effective solutions for the treatment of tuberculosis.Since the 1980s,various types of drug-resistant TB strains(XDR-TB、MDR-TB)have emerged in large numbers,while the progress of developing new drugs for overcoming such resistances was very slowly,which has brought tuberculosis treatment into a bottleneck.It’s an urgent need to search new anti-tuberculosis drugs with definite curative effect and short treatment period.It is well known that microorganisms can produce a wide variety of bioactive secondary metabolites,which is an important source for discovery of lead compounds.Until now,it’s still one of the most important ways to develop new anti-TB drugs from natural products.In this thesis,to search new active compounds against TB,we have conducted a screening in our own collection of natural products(1033 compounds)against Mycobacterium smegmatis(MSM),a model bacterium of Mycobacterium tuberculosis,which was used as the indicator bacterium.17 compounds with strong anti-MSM activity were identified.After screening the fermentation crude extracts of 465 strains(81 Marine fungi and 384 actinomycetes),20 best active strains were obtained,with a positive rate of 4.4%.Next,three strains with the best activities against MSM were picked for their secondary metabolites study.A total of 29 compounds,including three new compounds,were isolated and characterized after large-scale fermentation of such strains.Activity tracing showed that the major secondary metabolites of such strains were key bioactive components against MSM,including penicillitic acid,actinomycin D and Lobophorins.Firstly,we isolated 11 compounds from the Marine fungus Phoma mullirostrala WZW-F-22,which was fermented under the condition of potato-dextrose-agar(PDA)medium using seawater.These compounds are polyketones,alkaloids and benzoic acid derivatives,and two are new chemical entities.Secondly,we obtained 13 compounds from Streptomyces parvulus X3-5,a genus of actinomycetes from sweet potato rhizosphere,which was fermented under the condition of liquid SYP medium.These compounds include one cyclic peptide derivative,two phthalates,two benzene derivatives,three indoles and five cyclic dipeptides.Thirdly,5 glycosidic compounds of Lobophorin analogs were isolated from Streptomyces pactum SJD-52 fermented under the condition of liquid SYP medium.Among them,a new lobophorin analog was identified.