5W12

ADC-7 in complex with boronic acid transition state inhibitor EC04

Summary for 5W12

• Entry DOI: 10.2210/pdb5w12/pdb
• Related: 5W13 5W14
• Descriptor: Beta-lactamase, 3-[(2R)-2-borono-2-{[(thiophen-2-yl)acetyl]amino}ethyl]benzoic acid (3 entities in total)
• Functional Keywords: inhibitor, beta-lactamase, batsi, ec04, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Acinetobacter baumannii
• Total number of polymer chains: 4
• Total formula weight: 164566.65

Authors

Smolen, K.A.,Powers, R.A.,Wallar, B.J. (deposition date: 2017-06-01, release date: 2017-11-29, Last modification date: 2024-11-13)

Primary citation

Caselli, E.,Romagnoli, C.,Powers, R.A.,Taracila, M.A.,Bouza, A.A.,Swanson, H.C.,Smolen, K.A.,Fini, F.,Wallar, B.J.,Bonomo, R.A.,Prati, F.
Inhibition of Acinetobacter-Derived Cephalosporinase: Exploring the Carboxylate Recognition Site Using Novel beta-Lactamase Inhibitors.
ACS Infect Dis, 4:337-348, 2018

PubMed Abstract: Boronic acids are attracting a lot of attention as β-lactamase inhibitors, and in particular, compound S02030 ( K = 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 C/C 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, K = 44-115 nM), which is in contrast to the derivatives where the negative charge is omitted, such as the amide derivative 3d ( K = 224 nM) and the hydroxyamide derivative 3e ( K = 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.

PubMed: 29144725
DOI: 10.1021/acsinfecdis.7b00153

Experimental method

X-RAY DIFFRACTION (1.88 Å)