Quantum chemical prediction of effects of temperature on hydrolysis rate of penicillin under weakly acidic condition.

Temperature and pH are important factors affecting the hydrolysis of β-lactam antibiotics in water environments. However, the determination of hydrolysis kinetics and pathways is experimentally challenging, particularly in low temperature aqueous solutions because of time and cost constraints. In this study, an equation was employed to correct the Gibbs energy calculated in aqueous solutions by density functional theory methods to predict the effect of temperature on the hydrolysis kinetics and pathways of penicillin G. The results indicate that the most likely hydrolysis mechanism involves the opening of the β-lactam ring of anionic penicillin G protonated at the β-lactam oxygen atom with the participation of the carboxyl group and a water molecule. The results also suggest that the carboxyl group of β-lactam antibiotics was crucial for the hydrogen transfer. The predicted rate constants were of the same order of magnitude as the experimental values obtained under comparable pH and temperature conditions. Therefore, the quantum chemical methodology described herein can be potentially employed to determine pH- and temperature-based two-dimensional hydrolysis rate models, which can enable the prediction of the β-lactam antibiotics persistence in frigid waters.