Search For Antibiotic Molecules From Microbial Sources

In this thesis,we tried to discover antibiotic candidates from soil microbes collected in China,in order to alleviate the growing problem of antibiotic resistance.After screening 74 microbes,based on chemical profiles and antimicrobial activity,one bacterium(YM03-Y3)was selected for further investigation,and identified as Pseudomonas aurantiaca by 16 S r DNA sequencing.After extraction and purification,twelve compounds were isolated,including two known dialkylresorcinols(1,2),one new dialkylresorcinol-quinone dimer(4),one new furanone(5),and one new quinone(12).Seven additional compounds were isolated,but unfortunately due to low material and complex spectra,the structures could not be fully determined(3,6-11).An additional phenazine molecule(13)was identified in a study into the observed color changes on agar plates.During the course of the structure elucidation of compound 1,decomposition was observed on standing in CDCl3 for two days.Thus,additional experiments were designed to explore the identity of the decomposition products.Larger-scale decomposition studies led to the isolation and identification of three of the major decomposition products,which were elucidated as a new furanone(14),a known quinone(15),and a new quinone dimer(16)which suggested that several of the compounds(4,5,12)isolated previously might also be artifacts formed due to exposure to oxygen during the culturing,isolation,or storage process.All identified compounds were subjected to antimicrobial activity assays:dialkylresorcinols possessed significant activities against five Gram-positive bacterial pathogens,including methicillin-resistant Staphylococcus aureus.However,testing of the decomposition products revealed that they were also active,but weaker than natural products.Finally,feeding experiments shown that biosynthetic production of dialkylresorcinols can be influenced by the addition of caprylic acid,pelargonic acid and capric acid into the culture medium,which provided another direction to identify new molecules with precursor-directed biosynthesis.Overall,this research outlines the chemical diversity of Pseudomonas aurantiaca,and at the same time,the decomposition study on the antibacterial dialkylresorcinols provided more chemical diversity and helped to distinguish natural products from artifacts.This illustrates both the opportunities and challenges present in the discovery of new antibiotic molecules from microbial sources.Finally,has inspired more valuable research to pursue in the future,including semi-synthetic studies and additional drug discovery efforts.