Structures of FOX-4 Cephamycinase in Complex with Transition-State Analog Inhibitors

Lefurgy, Scott T.; Caselli, Emilia; Taracila, Magdalena A.; Malashkevich, Vladimir N.; Biju, Beena; Papp-Wallace, Krisztina M.; Bonanno, Jeffrey B.; Prati, Fabio; Almo, Steven C.; Bonomo, Robert A.

doi:10.3390/biom10050671

Title: Structures of FOX-4 Cephamycinase in Complex with Transition-State Analog Inhibitors

Journal Article · Mon Apr 27 00:00:00 EDT 2020 · Biomolecules

DOI:https://doi.org/10.3390/biom10050671· OSTI ID:1834814

Lefurgy, Scott T. ^[1];

^[2]; Taracila, Magdalena A. ^[3]; Malashkevich, Vladimir N. ^[4]; Biju, Beena ^[1]; Papp-Wallace, Krisztina M. ^[5]; Bonanno, Jeffrey B. ^[4]; Prati, Fabio ^[2]; Almo, Steven C. ^[4]; Bonomo, Robert A. ^[6]

Hofstra Univ., Hempstead, NY (United States). Dept. of Chemistry
Univ. of Modena and Reggio Emilia, Modena (Italy). Dept. of Life Sciences
Case Western Reserve Univ. School of Medicine, Cleveland, OH (United States). Dept. of Medicine; Louis Stokes Cleveland Dept. of Veterans Affairs Medical Center, Cleveland, OH (United States)
Albert Einstein College of Medicine, Bronx, NY (United States). Dept. of Biochemistry
Case Western Reserve Univ. School of Medicine, Cleveland, OH (United States). Dept. of Medicine. Dept. of Biochemistry; Louis Stokes Cleveland Dept. of Veterans Affairs Medical Center, Cleveland, OH (United States)
Case Western Reserve Univ. School of Medicine, Cleveland, OH (United States). Dept. of Medicine. Dept. of Biochemistry. Dept. of Pharmacology. Dept. of Molecular Biology and Microbiology. Dept. of Proteomics and Bioinformatics; Louis Stokes Cleveland Dept. of Veterans Affairs Medical Center, Cleveland, OH (United States); CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES), Cleveland, OH (United States)

Boronic acid transition-state analog inhibitors (BATSIs) are partners with β-lactam antibiotics for the treatment of complex bacterial infections. Herein, microbiological, biochemical, and structural findings on four BATSIs with the FOX-4 cephamycinase, a class C β-lactamase that rapidly hydrolyzes cefoxitin, are revealed. FOX-4 is an extended-spectrum class C cephalosporinase that demonstrates conformational flexibility when complexed with certain ligands. Like other β-lactamases of this class, studies on FOX-4 reveal important insights into structure–activity relationships. We show that SM23, a BATSI, shows both remarkable flexibility and affinity, binding similarly to other β-lactamases, yet retaining an IC₅₀ value < 0.1 μM. Our analyses open up new opportunities for the design of novel transition-state analogs of class C enzymes.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC)

OSTI ID:: 1834814

Journal Information:: Biomolecules, Vol. 10, Issue 5; ISSN 2218-273X

Publisher:: MDPICopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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59 BASIC BIOLOGICAL SCIENCES
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