title: β-Lactam antibiotic-degrading enzymes from non-pathogenic marine organisms: a potential threat to human health.
abstract: Metallo-β-lactamases (MBLs) are a family of Zn(II)-dependent enzymes that inactivate most of the commonly used β-lactam antibiotics. They have emerged as a major threat to global healthcare. Recently, we identified two novel MBL-like proteins, Maynooth IMipenemase-1 (MIM-1) and Maynooth IMipenemase-2 (MIM-2), in the marine organisms Novosphingobium pentaromativorans and Simiduia agarivorans, respectively. Here, we demonstrate that MIM-1 and MIM-2 have catalytic activities comparable to those of known MBLs, but from the pH dependence of their catalytic parameters it is evident that both enzymes differ with respect to their mechanisms, with MIM-1 preferring alkaline and MIM-2 acidic conditions. Both enzymes require Zn(II) but activity can also be reconstituted with other metal ions including Co(II), Mn(II), Cu(II) and Ca(II). Importantly, the substrate preference of MIM-1 and MIM-2 appears to be influenced by their metal ion composition. Since neither N. pentaromativorans nor S. agarivorans are human pathogens, the precise biological role(s) of MIM-1 and MIM-2 remains to be established. However, due to the similarity of at least some of their in vitro functional properties to those of known MBLs, MIM-1 and MIM-2 may provide essential structural insight that may guide the design of as of yet elusive clinically useful MBL inhibitors.
authors.affiliation: Department of Chemistry, Maynooth University, Maynooth, Co., Kildare, Ireland.
authors.forename: Manfredi
authors.initials: M
authors.lastname: Miraula
authors.forename: Jacob J
authors.initials: JJ
authors.lastname: Whitaker
authors.forename: Gerhard
authors.initials: G
authors.lastname: Schenk
authors.forename: Nataša
authors.initials: N
authors.lastname: Mitić
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism*; D020563:Gammaproteobacteria / Q000201:enzymology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D019216:Metals, Heavy / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D011634:Public Health; D042301:Sphingomonadaceae / Q000201:enzymology*; D065093:beta-Lactamase Inhibitors / Q000494:pharmacology; D001618:beta-Lactamases / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D047090:beta-Lactams / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D019216:Metals, Heavy; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams; D001618:beta-Lactamases