A Mechanism of Synergistic Effect of Streptomycin and Cefotaxime on CTX-M-15 Type β-lactamase Producing Strain of E. cloacae: A First Report

A bla(CTX-M-15) gene is one of the most prevalent resistant marker found in member of enterobacteriaceae. It encodes cefotaxime hydrolysing β-lactamase-15 (CTX-M-15) causing resistance against beta lactam antibiotics. Since single antibiotic therapy fails to control infection caused by multidrug resistance strain, therefore combination therapy was came into practice as an effective treatment. We have first time explained the mechanism where two antibiotics of different classes work against resistant strains. Binding parameters obtained by spectroscopic approach showed significant interaction and complex formation between drugs and CTX-M-15 enzyme with decreased k(sv) and k(q) values. CD analysis showed altered conformation and significant changes in alpha helical content of CTX-M-15 enzyme on interaction with streptomycin in combination with cephalosporin. Steady state kinetics revealed decrease in hydrolytic efficiency of enzyme to about 27% by cooperative binding behavior upon sequential treatment of enzyme with streptomycin and cefotaxime. Therefore, the study concludes that combination therapy against CTX-M-15 producing strain with Cefotaxime/Streptomycin in 1:10 molar ratio, decreases CTX-M-15 efficiency significantly because of the fact that streptomycin induced structural changes in CTX-M-15 hence cefotaxime was not properly bound on its active site for hydrolysis rather available for the target to inhibit bacterial cells.