The research proposed is directed toward the design, synthesis and evaluation of C3 feet-cephalosporin-amino acid and -peptide esters. These compounds are expected to serve as substrates for the Beta-lactamase enzymes of penicillin-resistant bacteria; and, as such, we anticipate that enzymatic processing will ultimately generate an amino aicd which is a mechanism-based inactivator (suicide substrate) for a second essential microbial enzyme, alanine racemase. Our immediate experimental goal is to determine in vitro whether the proposed synthetic targets will give inhibition of the purified racemase in a lactamase-dependent process. The attendant, long-term goal is to demonstrate that the known Beta-lactamase enzymological mechanism can be exploited for use as a selective drug-delivery system. Severl peptides are also proposed as synthetic targets. These incorporate amino acid residues into their structures which are suicide substrates for microbial enzymes. The peptides are expected to be transported by specific bacterial permeases with subsequent hydrolysis of the amide bond to generate the inactivating amino acid intracellularly. The peptides are further conceived to be antibacterials in their own right.
