%0 Journal Article %A Caselli, Emilia %A Romagnoli, Chiara %A Powers, Rachel A. %A Taracila, Magdalena A. %A Bouza, Alexandra A. %A Swanson, Hollister C. %A Smolen, Kali A. %A Fini, Francesco %A Wallar, Bradley J. %A Bonomo, Robert A. %A Prati, Fabio %D 2017 %T Inhibition of Acinetobacter-Derived Cephalosporinase: Exploring the Carboxylate Recognition Site Using Novel β‑Lactamase Inhibitors %U https://acs.figshare.com/articles/journal_contribution/Inhibition_of_i_Acinetobacter_i_-Derived_Cephalosporinase_Exploring_the_Carboxylate_Recognition_Site_Using_Novel_Lactamase_Inhibitors/5684443 %R 10.1021/acsinfecdis.7b00153.s001 %2 https://ndownloader.figshare.com/files/9950536 %K X-ray crystal structures %K R 2 side chain %K ADC -7 %K recognition %K compounds 3 c %K S 02030 %K EC %K β- lactamase inhibitors %K K i %K β- lactam antibiotic %K SM %K Carboxylate Recognition Site %K nM %K binding %K . baumannii %K compound S 02030 %K carboxy-R 2 side chain %X 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/C4 found 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 3ac, 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. %I ACS Publications