Man lacks a biochemical pathway for synthesis of aromatic amino acids. Thus, L-tyrosine, L-phenylalanine, L-tryptophan and vitamin-like derivatives of the pathway must be supplied externally. Pseudomonas aeruginosa requires this multi-branched, complicated pathway as a source of the latter essential metabolites as well as for pyocyanine pigment and iron-binding siderophores. Thus, an ideal basis exists for manipulation of the host-pathogen relationship since a multiplicity of enzyme targets exist in P. aeruginosa that are absent altogether in the host tissues. Additional applications are suggested by consideration of the metabolic interfaces of the pathway with carbohydrate metabolism and with catabolic networks. Aromatic endproducts are biochemically expensive to make and strategies of """"""""energy drain"""""""" that exhaust energy resources will be pursued using the mid-pathway inhibitor, glyphosate. Design of a stable substrate mimic of pathway dehydrogenase/dehydratase enzymes will be pursued. Modified genetic backgrounds or physiological conditions that block an anomalous phenomenon of endproduct depletion will be sought in order to facilitate mutant-isolation objectives. The possibility that """"""""catabolic"""""""" depletion is important to the pathobiological mode of P. aeruginosa will be evaluated. Continuation of the previous objectives to obtain a complete set of structural-gene and regulatory-gene mutants will be carried out with the objective of understanding gene-enzyme relationships from a comprehensive vantage point that includes physiological, biochemical and molecular-genetic levels. P. aeruginosa is noteworthy for its resistance to antimetabolite therapy. It is also commonly resistant to analog mimics of phenylalanine and tyrosine. Analog sensitivity can readily be achieved through manipulation of metabolic conditions. Specific understanding of the aromatic system may generalize to the nature of high antimetabolite resistance typical of P. aeruginosa.
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