Multi-target Control of Staphylococcus and Enterococcus

No class of antibiotic is completely effective against infections caused by species ofStaphylococcus and Enterococcus. Increasing incidence of multiple drug resistance among thestaphylococci and enterococci, as well as escalating nosocomial infection rates, complicates treatmentof severe infections. New antimicrobials are urgently needed. These pathogens possess a novel patternfor control of aromatic amino acid biosynthesis whereby multiple enzyme targets are potentiallyvulnerable to attack by a single compound. Prospects for selective action against the pathogen and notthe host are excellent since analogs of pathway intermediates that are absent in mammals will besynthesized analog structures will be sought which cause false feedback inhibition at the early-pathwaylevel 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, andobtaining compounds exhibiting a range of single and multiple-target effects. Effective classes of in vitroenzyme inhibitors identified in Phase I will be optimized in Phase II and then tested in vivo forantimicrobial efficacy.