%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 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.
%I ACS Publications