Cephalothin

These antibiotics, commonly used for the treatment of infections caused by Gram-positive cocci and Gram-negative bacilli, were each found to exhibit one reduction wave and were used for qualitative and quantitative analysis. Hall et a1.2 have carried out a more exhaustive electrochemical study on cephalosporin C derivatives which included cephalothin. They found a d.c. current at 10^-4 M concentrations which was constant in height over the pH range 0-4 and decreased to zero by pH 7-8. They reported that there was no observable reduction wave for the cephalothin anion in buffered solutions up to pH 8 but that a wave at -1.80 V existed in 0.1 M Et₄NC1O₄ supporting electrolyte

The group of Shoichet has published extensively in the field of boronic acid based b-lactamase inhibitors and based upon this previous experience, set out to identify a new, more potent inhibitor. Cephalothin, a widely used Cephalosporin antibiotic, possess a Ki of 320 nM versus AmpC type b-lacta-mases. Shoichet et al. illustrated that the closer the boronic acid resembles the natural substrate, the better the potency. The more the structure mimics the b-lactam of cephalothin, the greater the inhibition, with boronic acid 32 (Ki = 0.32 μM) the weakest. Addition of a stereogenic phenyl group 33, mimicking the dihydrothiazine of cephalothin, provides a 10-fold increase in potency (Ki = 0.035 μM). The insertion of a meta-carboxyphenyl moiety further improved the affinity for AmpC type b-lactamase to provide the most potent inhibitor yet described, boronic acid 34 (Ki = 0.001 μM).

The cephalosporin and peptide candidates selected for the synthesis of a prototypical conjugate were cephalothin and Bac8c, respectively. Cephalothin 1, containing a 39-acetate substituent and a thienyl side-chain, is a first generation cephalosporin with a broad spectrum of activity. Bac8c is a peptide amide of sequence RIWVIWRR-NH₂, obtained by optimisation of the bovine dodecapeptide bactenecin. The asset of this short 8-mer candidate is an activity against both Gram-negative and Gram-positive bacteria in the low micromolar range. Also, its number of residues, which remains close to the minimal length of a continuous epitope for an antigen, should prevent its immunogenicity and limit its production cost.