Boronic acids are attracting a lot of attention as β-lactamase inhibitors, and in particular, compound S02030 (Ki= 44 nM) proved to be a good lead compound against ADC-7 (Acinetobacter-derived cephalosporinase), one of the most significant resistance determinants in A. baumannii. The atomic structure of the ADC-7/S02030 complex highlighted the importance of critical structural determinants for recognition of the boronic acids. Herein, to elucidate the role in recognition of the R2-carboxylate, which mimics the C3/C4found in β-lactams, we designed, synthesized, and characterized six derivatives of S02030 (3a). Out of the six compounds, the best inhibitors proved to be those with an explicit negative charge (compounds 3a-c, 3h, and 3j, Ki= 44-115 nM), which is in contrast to the derivatives where the negative charge is omitted, such as the amide derivative 3d (Ki= 224 nM) and the hydroxyamide derivative 3e (Ki= 155 nM). To develop a structural characterization of inhibitor binding in the active site, the X-ray crystal structures of ADC-7 in a complex with compounds 3c, SM23, and EC04 were determined. All three compounds share the same structural features as in S02030 but only differ in the carboxy-R2 side chain, thereby providing the opportunity of exploring the distinct binding mode of the negatively charged R2 side chain. This cephalosporinase demonstrates a high degree of versatility in recognition, employing different residues to directly interact with the carboxylate, thus suggesting the existence of a "carboxylate binding region" rather than a binding site in ADC enzymes. Furthermore, this class of compounds was tested against resistant clinical strains of A. baumannii and are effective at inhibiting bacterial growth in conjunction with a β-lactam antibiotic.

Inhibition of Acinetobacter -Derived Cephalosporinase: Exploring the Carboxylate Recognition Site Using Novel β-Lactamase Inhibitors / Caselli, Emilia; Romagnoli, Chiara; Powers, Rachel A.; Taracila, Magdalena A.; Bouza, Alexandra A.; Swanson, Hollister C.; Smolen, Kali A.; Fini, Francesco; Wallar, Bradley J.; Bonomo, Robert A.; Prati, Fabio. - In: ACS INFECTIOUS DISEASES. - ISSN 2373-8227. - 4:3(2018), pp. 337-348. [10.1021/acsinfecdis.7b00153]

Inhibition of Acinetobacter -Derived Cephalosporinase: Exploring the Carboxylate Recognition Site Using Novel β-Lactamase Inhibitors

Caselli, Emilia;Romagnoli, Chiara;Fini, Francesco;Prati, Fabio
2018

Abstract

Boronic acids are attracting a lot of attention as β-lactamase inhibitors, and in particular, compound S02030 (Ki= 44 nM) proved to be a good lead compound against ADC-7 (Acinetobacter-derived cephalosporinase), one of the most significant resistance determinants in A. baumannii. The atomic structure of the ADC-7/S02030 complex highlighted the importance of critical structural determinants for recognition of the boronic acids. Herein, to elucidate the role in recognition of the R2-carboxylate, which mimics the C3/C4found in β-lactams, we designed, synthesized, and characterized six derivatives of S02030 (3a). Out of the six compounds, the best inhibitors proved to be those with an explicit negative charge (compounds 3a-c, 3h, and 3j, Ki= 44-115 nM), which is in contrast to the derivatives where the negative charge is omitted, such as the amide derivative 3d (Ki= 224 nM) and the hydroxyamide derivative 3e (Ki= 155 nM). To develop a structural characterization of inhibitor binding in the active site, the X-ray crystal structures of ADC-7 in a complex with compounds 3c, SM23, and EC04 were determined. All three compounds share the same structural features as in S02030 but only differ in the carboxy-R2 side chain, thereby providing the opportunity of exploring the distinct binding mode of the negatively charged R2 side chain. This cephalosporinase demonstrates a high degree of versatility in recognition, employing different residues to directly interact with the carboxylate, thus suggesting the existence of a "carboxylate binding region" rather than a binding site in ADC enzymes. Furthermore, this class of compounds was tested against resistant clinical strains of A. baumannii and are effective at inhibiting bacterial growth in conjunction with a β-lactam antibiotic.
8-dic-2017
4
3
337
348
Inhibition of Acinetobacter -Derived Cephalosporinase: Exploring the Carboxylate Recognition Site Using Novel β-Lactamase Inhibitors / Caselli, Emilia; Romagnoli, Chiara; Powers, Rachel A.; Taracila, Magdalena A.; Bouza, Alexandra A.; Swanson, Hollister C.; Smolen, Kali A.; Fini, Francesco; Wallar, Bradley J.; Bonomo, Robert A.; Prati, Fabio. - In: ACS INFECTIOUS DISEASES. - ISSN 2373-8227. - 4:3(2018), pp. 337-348. [10.1021/acsinfecdis.7b00153]
Caselli, Emilia; Romagnoli, Chiara; Powers, Rachel A.; Taracila, Magdalena A.; Bouza, Alexandra A.; Swanson, Hollister C.; Smolen, Kali A.; Fini, Francesco; Wallar, Bradley J.; Bonomo, Robert A.; Prati, Fabio
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1157542
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