A theoretical approach for the acylation/deacylation mechanisms of avibactam in the reversible inhibition of KPC-2

Klebsiella pneumoniae carbapenemase (KPC-2) is the most commonly encountered class A β-lactamase variant worldwide, which confer high-level resistance to most available antibiotics. In this article we address the issue by a combined approach involving molecular dynamics simulations and hybrid quantum mechanics/molecular mechanics calculations. The study contributes to improve the understanding, at molecular level, of the acylation and deacylation stages of avibactam involved in the inhibition of KPC-2. The results show that both mechanisms, acylation and deacylation, the reaction occur via the formation of a tetrahedral intermediate. The formation of this intermediate corresponds to the rate limiting stage. The activation barriers are 19.5 kcal/mol and 23.0 kcal/mol for the acylation and deacylation stages, respectively. The associated rate constants calculated, using the Eyring equation, are 1.2 × 10(−1) and 3.9 × 10(−4) (s(−1)). These values allow estimating a value of 3.3 × 10(−3) for the inhibition constant, in good agreement with the experimental value. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10822-021-00408-3.