title: The sequence-activity relationship between metallo-β-lactamases IMP-1, IMP-6, and IMP-25 suggests an evolutionary adaptation to meropenem exposure.
abstract: Metallo-β-lactamases are important determinants of antibacterial resistance. In this study, we investigate the sequence-activity relationship between the closely related enzymes IMP-1, IMP-6, and IMP-25. While IMP-1 is the more efficient enzyme across the overall spectrum of tested β-lactam antibacterial agents, IMP-6 and IMP-25 seem to have evolved to specifically inactivate the newer carbapenem meropenem. Molecular modeling indicates that the G235S mutation distinguishing IMP-25 from IMP-1 and IMP-6 may affect enzyme activity via Asn233.
authors.affiliation: Department of Pharmaceutical Sciences, Western University of Health Sciences, Pomona, CA, USA.
authors.forename: Eleanor M
authors.initials: EM
authors.lastname: Liu
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Pegg
authors.forename: Peter
authors.initials: P
authors.lastname: Oelschlaeger
mesh_terms: D000220:Adaptation, Biological / Q000235:genetics* / Q000502:physiology; D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000737:chemistry / Q000187:drug effects / Q000235:genetics*; D005075:Biological Evolution; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D007700:Kinetics; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D013845:Thienamycins / Q000494:pharmacology*; D001618:beta-Lactamases / Q000187:drug effects* / Q000235:genetics*; D047090:beta-Lactams / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D013845:Thienamycins; D047090:beta-Lactams; C409201:beta-lactamase IMP-1; D001618:beta-Lactamases; C578529:beta-lactamase IMP-25, Pseumonas aeruginosa; D000077731:Meropenem