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.

Structures of FOX-4 cephamycinase in complex with transition-state analog inhibitors / Lefurgy, S. T.; Caselli, E.; Taracila, M. A.; Malashkevich, V. N.; Biju, B.; Papp-Wallace, K. M.; Bonanno, J. B.; Prati, F.; Almo, S. C.; Bonomo, R. A.. - In: BIOMOLECULES. - ISSN 2218-273X. - 10:5(2020), pp. 671-671. [10.3390/biom10050671]

Structures of FOX-4 cephamycinase in complex with transition-state analog inhibitors

Caselli E.;Prati F.;
2020

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.
2020
10
5
671
671
Structures of FOX-4 cephamycinase in complex with transition-state analog inhibitors / Lefurgy, S. T.; Caselli, E.; Taracila, M. A.; Malashkevich, V. N.; Biju, B.; Papp-Wallace, K. M.; Bonanno, J. B.; Prati, F.; Almo, S. C.; Bonomo, R. A.. - In: BIOMOLECULES. - ISSN 2218-273X. - 10:5(2020), pp. 671-671. [10.3390/biom10050671]
Lefurgy, S. T.; Caselli, E.; Taracila, M. A.; Malashkevich, V. N.; Biju, B.; Papp-Wallace, K. M.; Bonanno, J. B.; Prati, F.; Almo, S. C.; Bonomo, R. A.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1202392
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