Syn2190, a
monobactam derivative containing 1,5-dihydroxy-4-pyridone as the C-3 side chain, is a potent inhibitor of group 1
beta-lactamase. The concentrations of inhibitor needed to reduce the initial rate of hydrolysis of substrate by 50% for
Syn2190 against these
enzymes were in the range of 0.002 to 0.01 microM. These values were 220- to 850-fold lower than those of
tazobactam.
Syn2190 showed in vitro synergy with
ceftazidime and
cefpirome. This synergy was dependent on the concentration of the inhibitor against group 1
beta-lactamase-producing strains, such as Pseudomonas aeruginosa, Enterobacter cloacae, Citrobacter freundii, and Morganella morganii. However, against
beta-lactamase-derepressed mutants of P. aeruginosa, the MICs of
ceftazidime plus
Syn2190 were not affected by the amount of
beta-lactamase, and the values were the same for the parent strains. The MICs at which 50% of isolates are inhibited (MIC(50)s) of
ceftazidime plus
Syn2190 were 2- to 16-fold lower than those of
ceftazidime alone for
ceftazidime-resistant, clinically isolated gram-negative bacteria. Similarly, the MIC(50)s of
cefpirome plus
Syn2190 were two- to eightfold lower for
cefpirome-resistant clinical isolates. The synergies of
Syn2190 plus
ceftazidime or
cefpirome observed in vitro were also reflected in vivo.
Syn2190 improved the efficacies of both
cephalosporins in both a murine systemic
infection model with
cephalosporin-resistant rods and
urinary tract infection models with
cephalosporin-resistant P. aeruginosa.