Our research interests are broadly in bioorganic and natural products chemistry; biosynthesis of microbial secondary metabolites; and the interface of molecular genetics, enzymology, and chemistry to create and develop novel pharmaceutically active leads. Currently, a number of research projects are being pursued in our laboratory:
The C7N aminocyclitol family of natural products, represented by the alpha-glucosidase inhibitor acarbose and the antifungal antibiotic validamycin, has traditionally been known as a group of pseudoaminooligosaccharides of bacterial origin that exhibit potent sugar hydrolase inhibitory activities. However, more recent discoveries of secondary metabolites belonging to this family of natural products indicate a broader scope to their structural diversity and biological activity. The pyralomicins, antibiotics isolated from Nonomuraea spiralis and the cetoniacytones, anti-tumor agents isolated from an endosymbiotic Actinomyces sp. living in the intestines of an insect, Cetonia aureata, are two examples of unusual subgroups of this family. Despite their unusual structure, the C7N units in their molecules appear to be derived via the pentose phosphate pathway as have also been shown for acarbose and validamycin. Further insights about their biosynthesis are critical for their production and further development, which are being pursued in this project.
Tuberculosis (TB) infects one third of the world population and kills approximately 2 million people each year. This number is steadily increasing primarily due to the increase of the deadly combination TB/HIV cases coupled with the poor health services in certain countries, the emergence of multi drug-resistant TB, and the rapid exchange among world populations that travel and carry around this contagious disease. If control is not further improved, it is estimated that during the next two decades, approximately 1 billion people will be newly infected, over 150 million people will develop active disease, and 36 million will die of TB. Therefore, new drug discovery and the continued development of existing drugs to combat TB is a matter of emergency. To this end, we have initiated a study toward the discovery of new anti-tubercular drugs. The study includes utilization of molecular genetics and synthetic approach to generate novel derivatives of the anti-tubercular drug rifamycin.
The myxobacteria have proven to be a rich source of novel natural products, as a wide variety of biologically active substances are produced by these microorganisms. These include the electron transport inhibitors myxothiazol, melithiazol, and myxalamid. These compounds are biosynthesized by a unique combination of polyketide synthases (PKS) and nonribosomal peptide synthetases (NRPS). The PKS operating in myxalamid biosynthesis is believed to be rather flexible in terms of its substrate-specificity as indicated by its ability to produce a number of myxalamids from various starter units. This fairly relaxed enzyme raises the possibility of in-vivo modification of myxalamid using exogenous unnatural starter units to give rise to novel biologically active analogs. A major recent discovery in another aspect of this project is the identification of a novel shunt pathway from HMG-CoA to isovaleryl-CoA, precursor of myxothiazol and BCFA in Stigmatella aurantiaca. Identification of this alternative pathway and its corresponding enzymes is critical for the understanding of its regulation and function in myxobacteria, particularly in functions associated with branched-chain fatty acids, e.g., the cell membrane fluidity and the myxobacterial cell-cell communication signal. It could also be a model for the investigation of similar pathways in various pathogenic microorganisms that contain BCFA as the predominant fatty acid species.
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