Molecular insights into avibactam mediated class C β-lactamase inhibition: competition between reverse acylation and hydrolysis through desulfation.

Avibactam is one of the promising next generation β-lactamase inhibitors due to its exceptional inhibition against wide-spectrum serine β-lactamases. The unusual reversible acylation mechanism has particularly gained interest to explain the inhibition mechanism of avibactam. We explore the mechanism of acylation and deacylation involving avibactam in class-C β-lactamases (CBLs) through hybrid quantum mechanical/molecular mechanical (QM/MM) enhanced sampling molecular dynamics (MD) simulations. Based on these computations, we probe the kinetic stability of the acyl-enzyme complex formed by avibactam and CBLs, thereby gaining molecular level insights into the avibactam-mediated inhibition of CBLs.