MBL-fold metallo-hydrolases are zinc-dependent enzymes characterized by a conserved αβ/βα sandwich structure known as the metallo-β-lactamase (MBL) fold. Among them, metallo-β-lactamases hydrolyze β-lactam antibiotics using one or two Zn²⁺ ions, rendering many clinically important drugs, including carbapenems, ineffective. Unlike serine β-lactamases, MBLs are not inhibited by classical β-lactamase inhibitors, making them a major challenge in antimicrobial therapy.
Environmental metallo-hydrolases are also considered potential reservoirs for the evolution of novel β-lactamases. Our group is currently working on the structure-function relationship of such enzymes to decipher the molecular factors for their vast substrate specificity.
Currently, the MBL fold metallohydrolase from Gram-negative pathogens like Klebsiella pneumoniae (Kmh-1) and Vibrio vulnificus (Vmh-1) are in focus. By engaging approaches such as X-ray crystallography, mutational analysis and molecular dynamics simulation we are trying to pinpoint the mechanistic insights of those enzymes. Novelty lies in their active sites where they can accommodate diverse substrates and exhibit activity in presence of multiple metals.
As future prospects, our study may aid the discovery of broad-spectrum MBL inhibitors and surveillance of environmental resistance reservoirs. Advanced approaches including molecular dynamics, metagenomics, and machine learning-based prediction of resistance evolution may aid in understanding substrate specificity, enzyme adaptability, and inhibitor design. We are hopeful that our studies will be essential for combating the growing threat posed by MBL-mediated antibiotic resistance.