Boronic Acid Transition State Inhibitors as Potent Inactivators of KPC and CTX-M β-Lactamases: Biochemical and Structural Analyses.

Autor: Alsenani TA; Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA., Rodríguez MM; Universidad de Buenos Aires, Facultad de Farmacia y Bioquimica, Instituto de Investigaciones en Bacteriologia y Virologia Molecular, Buenos Aires, Argentina.; Consejo Nacional de Investigaciones Científicas y Tecnicas, Buenos Aires, Argentina., Ghiglione B; Universidad de Buenos Aires, Facultad de Farmacia y Bioquimica, Instituto de Investigaciones en Bacteriologia y Virologia Molecular, Buenos Aires, Argentina.; Consejo Nacional de Investigaciones Científicas y Tecnicas, Buenos Aires, Argentina., Taracila MA; Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.; Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA., Mojica MF; Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.; Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.; CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology, Cleveland, Ohio, USA., Rojas LJ; Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.; Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.; CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology, Cleveland, Ohio, USA., Hujer AM; Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.; Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA., Gutkind G; Universidad de Buenos Aires, Facultad de Farmacia y Bioquimica, Instituto de Investigaciones en Bacteriologia y Virologia Molecular, Buenos Aires, Argentina.; Consejo Nacional de Investigaciones Científicas y Tecnicas, Buenos Aires, Argentina., Bethel CR; Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA., Rather PN; Department of Microbiology and Immunology, Emory University, Atlanta, Georgia, USA.; Emory Antibiotic Resistance Center, Emory University, Atlanta, Georgia, USA.; Research Service, Atlanta VA Medical Center, Decatur, Georgia, USA., Introvigne ML; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy., Prati F; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy., Caselli E; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy., Power P; Universidad de Buenos Aires, Facultad de Farmacia y Bioquimica, Instituto de Investigaciones en Bacteriologia y Virologia Molecular, Buenos Aires, Argentina.; Consejo Nacional de Investigaciones Científicas y Tecnicas, Buenos Aires, Argentina., van den Akker F; Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA., Bonomo RA; Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.; Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.; Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.; Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.; CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology, Cleveland, Ohio, USA.; Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.; Department of Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Jazyk: angličtina
Zdroj: Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2023 Jan 24; Vol. 67 (1), pp. e0093022. Date of Electronic Publication: 2023 Jan 05.
DOI: 10.1128/aac.00930-22
Abstrakt: Design of novel β-lactamase inhibitors (BLIs) is one of the currently accepted strategies to combat the threat of cephalosporin and carbapenem resistance in Gram-negative bacteria. B oronic a cid t ransition s tate i nhibitors (BATSIs) are competitive, reversible BLIs that offer promise as novel therapeutic agents. In this study, the activities of two α-amido-β-triazolylethaneboronic acid transition state inhibitors (S02030 and MB_076) targeting representative KPC (KPC-2) and CTX-M (CTX-M-96, a CTX-M-15-type extended-spectrum β-lactamase [ESBL]) β-lactamases were evaluated. The 50% inhibitory concentrations (IC 50 s) for both inhibitors were measured in the nanomolar range (2 to 135 nM). For S02030, the k 2 / K for CTX-M-96 (24,000 M -1 s -1 ) was twice the reported value for KPC-2 (12,000 M -1 s -1 ); for MB_076, the k 2 / K values ranged from 1,200 M -1 s -1 (KPC-2) to 3,900 M -1 s -1 (CTX-M-96). Crystal structures of KPC-2 with MB_076 (1.38-Å resolution) and S02030 and the in silico models of CTX-M-96 with these two BATSIs show that interaction in the CTX-M-96-S02030 and CTX-M-96-MB_076 complexes were overall equivalent to that observed for the crystallographic structure of KPC-2-S02030 and KPC-2-MB_076. The tetrahedral interaction surrounding the boron atom from S02030 and MB_076 creates a favorable hydrogen bonding network with S70, S130, N132, N170, and S237. However, the changes from W105 in KPC-2 to Y105 in CTX-M-96 and the missing residue R220 in CTX-M-96 alter the arrangement of the inhibitors in the active site of CTX-M-96, partially explaining the difference in kinetic parameters. The novel BATSI scaffolds studied here advance our understanding of structure-activity relationships (SARs) and illustrate the importance of new approaches to β-lactamase inhibitor design.
Databáze: MEDLINE
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