Inhibition of Acinetobacter-Derived Cephalosporinase: Exploring the Carboxylate Recognition Site Using Novel ß-Lactamase Inhibitors.
ACS Infect Dis
; 4(3): 337-348, 2018 03 09.
Article
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| MEDLINE
| ID: mdl-29144725
ABSTRACT
Boronic acids are attracting a lot of attention as ß-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/C4 found in ß-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 ß-lactam antibiotic.
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Bases de datos:
MEDLINE
Asunto principal:
Acinetobacter
/
Ácidos Borónicos
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Cefalosporinasa
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Inhibidores de beta-Lactamasas
Idioma:
En
Revista:
ACS Infect Dis
Año:
2018
Tipo del documento:
Article
País de afiliación:
Italia