Structural compatibility between β‐lactams and substrate binding pockets of IMP ‐1 and NDM ‐1 determines the substrate spectrum

Abstract

The global spread of infectious diseases is exacerbated by rising antimicrobial resistance, with Metallo‐β‐lactamases (MBLs) contributing significantly by inactivating β‐lactam antibiotics. The enzyme's substrate spectrum is usually determined by structural compatibility between the substrate‐binding pocket (SBP) and the substrate. We studied the structural compatibility between the SBPs of IMP‐1 and NDM‐1 and six β‐lactam substrates, and the correlation between compatibility and hydrolytic activity. MBLs have a conserved SBP surrounded by three external loops. The SBP contains catalytic zinc‐binding sites at the center and R _α and R _β pockets on both sides. IMP‐1 has narrower R _α and wider‐open R _β pockets, while NDM‐1 has broader R _α and less‐open R _β pockets. Different classes of β‐lactams show distinct structural characteristics in the core rings and both side chains. We performed enzyme kinetics and molecular docking studies. Results show that higher structural compatibility, especially in the tighter R _α pocket, is important for hydrolytic activity. The structural compatibility study will help clarify the substrate‐spectrum profile of MBLs across diverse β‐lactams.