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The most prevalent and important mechanism of bacterial resistance to &beta-lactam antibiotics, is the production of &beta-lactamase enzymes which inactivate these drugs by the hydrolytic cleavage of the four-membered &beta-lactam ring during two steps which is including the nucleophilic attack of the bridging hydroxide ion on the substrate and eventual protonation of the leaving amine group. During this reaction, metal ions play an important role in the catalytic process. Despite the availability of &beta-lactamase crystallographic structures, their mechanism of action is still unclear and no clinically useful inhibitors of these enzymes have been reported. Density functional theory (DFT) using B3LYP and 6-31G, 6-31G* and 6-311G** basis sets have been employed to calculate the details of electronic structure and electronic energy of catalytic reaction of CcrA enzyme active center from metallo-&beta-lactamase enzymes (M&betaLs), penicillin from &beta-lactam antibiotics, and the formed complexes including ES, ETS₁, EI₁, EI₂, ETS₂ and EP respectively, has been used. Also all the thermodynamic functions including ∆Hº, ∆Sº and ∆Gº to form two transition states, ETS₁ and ETS₂, and for the total reaction are evaluated at 25 °C, 31 °C, 37 °C and 40 °C and 1 atmosphere pressure. In all calculations solvent effects have been considered by using PCM method for water, ethanol, protein environment, nitro methane and carbon tetrachloride. Finally this reaction proceeds during an exothermic and spontaneous process, and the first step, the nucleophilic attack of the bridging hydroxide ion on the substrate, is the rate-limiting step

Keywords: β-Lactam antibiotics, Metallo-β-lactamase enzymes (MβLs), CcrA enzyme, Penicillin, Thermodynamic functions, QM calculations

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