No class of antibiotic is completely effective against infections caused by species of Staphylococcus and Enterococcus. Increasing incidence of multiple drug resistance among the staphylococci and enterococci, as well as escalating nosocomial infection rates, complicates treatment of severe infections. New antimicrobials are urgently needed. These pathogens possess a novel pattern for control of aromatic amino acid biosynthesis whereby multiple enzyme targets are potentially vulnerable to attack by a single compound. Prospects for selective action against the pathogen and not the host are excellent since analogs of pathway intermediates that are absent in mammals will be synthesized analog structures will be sought which cause false feedback inhibition at the early-pathway level in addition to causing competitive inhibition of substrate-depleted mid- pathway enzymes. Chemical design of inhibitors will be oriented to objectives of optimizing stability, transport, and obtaining compounds exhibiting a range of single and multiple-target effects. Effective classes of in vitro enzyme inhibitors identified in Phase I will be optimized in Phase II and then tested in vivo for antimicrobial efficacy.
