Natural product research during the last few decades has yielded thousands of novel, bioactive organic compounds from the marine environment. However, little has been done to explore the application of marine natural products for the treatment of the AIDS opportunistic infections Mycobacterium sp. The primary goal of this project is the gram scale isolation of those marine structural classes identified as having significant activity against Mycobacterium in vitro. The natural product scaffolds will be utilized for biological evaluation, structural modifications and lead optimization, The marine natural products of interest include: manzamine alkaloids; uranidine alkaloids; C19 hydroxy steroids; tetrabromo spirocyclohexadienylisoxazolines; scalarin sesterterpenoids and shikimate-sesquiterpenes. The isolation and structure determination of both the major and minor natural product constituents of these marine structural classes will be completed. Pure natural, semisynthetic and biotransformation products from these six unique structural classes will be evaluated for biological activity at the Tuberculosis Antimicrobial Acquisition & Coordinating Facilities (TAACF). Lead optimization studies of the active scaffolds isolated in 50mg or greater quantities (1 gram target isolation) will be completed using combinatorial/parallel synthesis and microbial transformations (including combinatorial). The marine natural products will be purified using preparative and semi-preparative high pressure liquid chromatography (HPLC), independently and interfaced with NMR and FTMS. The chemical structures of biologically active products will be determined with the use of 2D NMR and FTMS. Structure activity relationships (SAR) will be completed using the biological results generated from natural, semisynthetic and bioconversion products. In addition the microbial metabolism studies will provide valuable information regarding the metabolic fate of these lead marine derived anti-TB structural classes. Optimized marine natural product derived leads will be scaled-up for in vivo anti-TB assays in mice. Tuberculosis is an extremely serious disease infecting an estimated one-third of the world's population. The rapid spread of drug-resistant strains of this bacillus in the last several years has created an urgent need for novel therapeutic agents with new modes of action to counter this impending threat. The six marine-derived structural classes described in this proposal will undergo thorough preclinical evaluation to determine their potential as drug leads for the treatment of TB.
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