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- Title
Structures of FOX-4 Cephamycinase in Complex with Transition-State Analog Inhibitors.
- Authors
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.
- Abstract
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.
- Subjects
BORONIC acids; BETA lactamases; STRUCTURE-activity relationships; BACTERIAL diseases; BETA lactam antibiotics; ANTIBIOTICS
- Publication
Biomolecules (2218-273X), 2020, Vol 10, Issue 5, p671
- ISSN
2218-273X
- Publication type
Article
- DOI
10.3390/biom10050671