title: Class A carbapenemase FPH-1 from Francisella philomiragia.
abstract: FPH-1 is a new class A carbapenemase from Francisella philomiragia. It produces high-level resistance to penicillins and the narrow-spectrum cephalosporin cephalothin and hydrolyzes these β-lactam antibiotics with catalytic efficiencies of 10(6) to 10(7) M(-1) s(-1). When expressed in Escherichia coli, the enzyme confers resistance to clavulanic acid, tazobactam, and sulbactam and has K(i) values of 7.5, 4, and 220 μM, respectively, against these inhibitors. FPH-1 increases the MIC of the monobactam aztreonam 256-fold and the MIC of the broad-spectrum cephalosporin ceftazidime 128-fold, while the MIC of cefoxitin remains unchanged. MICs of the carbapenem antibiotics imipenem, meropenem, doripenem, and ertapenem are elevated 8-, 8-, 16-, and 64-fold, respectively, against an E. coli JM83 strain producing the FPH-1 carbapenemase. The catalytic efficiencies of the enzyme against carbapenems are in the range of 10(4) to 10(5) M(-1) s(-1). FPH-1 is 77% identical to the FTU-1 β-lactamase from Francisella tularensis and has low amino acid sequence identity with other class A β-lactamases. Together with FTU-1, FPH-1 constitutes a new branch of the prolific and ever-expanding class A β-lactamase tree.
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Toth
authors.forename: Viktoria
authors.initials: V
authors.lastname: Vakulenko
authors.forename: Nuno T
authors.initials: NT
authors.lastname: Antunes
authors.forename: Hilary
authors.initials: H
authors.lastname: Frase
authors.forename: Sergei B
authors.initials: SB
authors.lastname: Vakulenko
mesh_terms: D001426:Bacterial Proteins / Q000378:metabolism*; D015780:Carbapenems / Q000494:pharmacology; D019818:Clavulanic Acid / Q000494:pharmacology; D000077726:Doripenem; D000077727:Ertapenem; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D005603:Francisella / Q000187:drug effects* / Q000201:enzymology*; D015378:Imipenem / Q000494:pharmacology; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D010397:Penicillanic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D013407:Sulbactam / Q000494:pharmacology; D000078142:Tazobactam; D013845:Thienamycins / Q000494:pharmacology; D001618:beta-Lactamases / Q000378:metabolism*; D047090:beta-Lactams / Q000494:pharmacology
chemical_list: D001426:Bacterial Proteins; D015780:Carbapenems; D013845:Thienamycins; D047090:beta-Lactams; D019818:Clavulanic Acid; D015378:Imipenem; D010397:Penicillanic Acid; D000077726:Doripenem; D001618:beta-Lactamases; C063912:carbapenemase; D000077731:Meropenem; D000077727:Ertapenem; D013407:Sulbactam; D000078142:Tazobactam