The emergence of antibiotic resistance is a major challenge in the clinical setting. Stenotrophomonas maltophilia is an emerging gram-negative bacterium that produces Metallo-b-lactamase (MBL) L1. Metallo-beta-Lactamases (MBLs) is a class B β-lactamases that hydrolyze β-lactam antibiotics. The β-lactam antibiotics, which include antibiotics such as penicillin, inhibit bacterial transpeptidases involved in cell-wall biosynthesis. Bacteria produce MBLs as a mechanism to neutralize the antibiotic’s effect on the bacterial cell.
Several structures of MBLs have been commonly studied. NDM1 (New Delhi Metallo-b-lactamase-1) is a widely studied lactamase. L1 lactamase, however, shares only 22% sequence identity with NDM1, structurally these are very similar. One of the key differences in the structures is observed in the vicinity of the active site where antibiotics interact. Compared to NDM1, L1 active site is more accessible to antibiotics and thus show higher activity. An important feature of the active site of L1 is the Zinc ions coordinated by a water molecule. These two-metal binding sites consist of three histidine residues coordinated by the first metal ion and cysteine, histidine, and aspartic acid-binding the second metal ion. Understanding the interaction of the antibiotics with L1 and others of its class using structural and biochemical assays can provide a wealth of information that can aid design novel antibiotics to fight challenging bacterial strains both in and out of the clinical setting.
Reference
Kim, Y., Maltseva, N., Wilamowski, M., Tesar, C., Endres, M., & Joachimiak, A. (2020). Structural and biochemical analysis of the metallo-β-lactamase L1 from emerging pathogen Stenotrophomonas maltophilia revealed the subtle but distinct di-metal scaffold for catalytic activity. Protein Science, 29(3), 723–743. https://doi.org/10.1002/pro.3804