That Beta-lactam antibiotics account for approximately 10% of world-wide ethical drugs sales attests to their importance in combatting bacterial infections in man. In this renewal application a research program is detailed to continue biosynthetic studies of (1) the monocyclic Beta-lactams represented by the nocardicins and the monobactams, (2) the important lactamase inhibitor, clavulanic acid, and the related, antipodal clavams, and (3) the carbapenems using carbapenem-3-carboxylate, the simplest structurally of this family, as the experimental system. Groundwork successfully laid in the current grant period in cell- free studies and enzymology will be expanded and applied with ongoing synthetic, spectroscopic and stereochemical approaches to understanding the fundamental biosynthetic steps responsible for Beta-lactam antibiotic formation. The knowledge to be gained in studies of this kind will lead to improved production of these valuable commodities through incorporation of multiple copies of key biosynthetic genes in commercial fermentation strains, and could in the future provide modified structural types with improved pharmacological properties.
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