title: IMP-43 and IMP-44 metallo-β-lactamases with increased carbapenemase activities in multidrug-resistant Pseudomonas aeruginosa.
abstract: Two novel IMP-type metallo-β-lactamase variants, IMP-43 and IMP-44, were identified in multidrug-resistant Pseudomonas aeruginosa isolates obtained in medical settings in Japan. Analysis of their predicted amino acid sequences revealed that IMP-43 had an amino acid substitution (Val67Phe) compared with IMP-7 and that IMP-44 had two substitutions (Val67Phe and Phe87Ser) compared with IMP-11. The amino acid residue at position 67 is located at the end of a loop close to the active site, consisting of residues 60 to 66 in IMP-1, and the amino acid residue at position 87 forms a hydrophobic patch close to the active site with other amino acids. An Escherichia coli strain expressing blaIMP-43 was more resistant to doripenem and meropenem but not to imipenem than one expressing blaIMP-7. An E. coli strain expressing blaIMP-44 was more resistant to doripenem, imipenem and meropenem than one expressing blaIMP-11. IMP-43 had more efficient catalytic activities against all three carbapenems than IMP-7, indicating that the Val67Phe substitution contributed to increased catalytic activities against carbapenems. IMP-44 had more efficient catalytic activities against all carbapenems tested than IMP-11, as well as increased activities compared with IMP-43, indicating that both the Val67Phe and Phe87Ser substitutions contributed to increased catalytic activities against carbapenems.
authors.affiliation: Department of Infectious Diseases, Research Institute, National Center for Global Health and Medicine, Shinjuku, Tokyo, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Tada
authors.forename: Tohru
authors.initials: T
authors.lastname: Miyoshi-Akiyama
authors.forename: Kayo
authors.initials: K
authors.lastname: Shimada
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shimojima
authors.forename: Teruo
authors.initials: T
authors.lastname: Kirikae
mesh_terms: D019943:Amino Acid Substitution; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D015780:Carbapenems / Q000494:pharmacology; D020134:Catalytic Domain; D000077726:Doripenem; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects*; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D015378:Imipenem / Q000494:pharmacology; D007564:Japan / Q000453:epidemiology; D000077731:Meropenem; D010802:Phylogeny; D010957:Plasmids / Q000737:chemistry; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000453:epidemiology / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000145:classification / Q000187:drug effects* / Q000201:enzymology* / Q000302:isolation & purification; D013329:Structure-Activity Relationship; D013845:Thienamycins / Q000494:pharmacology; D001618:beta-Lactamases / Q000737:chemistry / Q000145:classification / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D013845:Thienamycins; D015378:Imipenem; D000077726:Doripenem; D001618:beta-Lactamases; D000077731:Meropenem