6TZF

ADC-7 in complex with boronic acid transition state inhibitor S17079

Summary for 6TZF

• Entry DOI: 10.2210/pdb6tzf/pdb
• Descriptor: Beta-lactamase, 3-(1-{[hydroxy(phosphonooxy)boranyl]methyl}-1H-1,2,3-triazol-4-yl)benzoic acid (3 entities in total)
• Functional Keywords: inhibitor, beta-lactamase, batsi, adc-7, hydrolase
• Biological source: Acinetobacter baumannii
• Total number of polymer chains: 4
• Total formula weight: 164541.96

Authors

Fish, E.R.,Powers, R.A.,Wallar, B.J. (deposition date: 2019-08-12, release date: 2020-06-24, Last modification date: 2024-10-16)

Primary citation

Caselli, E.,Fini, F.,Introvigne, M.L.,Stucchi, M.,Taracila, M.A.,Fish, E.R.,Smolen, K.A.,Rather, P.N.,Powers, R.A.,Wallar, B.J.,Bonomo, R.A.,Prati, F.
1,2,3-Triazolylmethaneboronate: A Structure Activity Relationship Study of a Class of beta-Lactamase Inhibitors againstAcinetobacter baumanniiCephalosporinase.
Acs Infect Dis., 6:1965-1975, 2020

PubMed Abstract: Boronic acid transition state inhibitors (BATSIs) are known reversible covalent inhibitors of serine β-lactamases. The selectivity and high potency of specific BATSIs bearing an amide side chain mimicking the β-lactam's amide side chain are an established and recognized synthetic strategy. Herein, we describe a new class of BATSIs where the amide group is replaced by a bioisostere triazole; these compounds were designed as molecular probes. To this end, a library of 26 α-triazolylmethaneboronic acids was synthesized and tested against the clinically concerning -derived cephalosporinase, ADC-7. In steady state analyses, these compounds demonstrated values ranging from 90 nM to 38 μM (±10%). Five compounds were crystallized in complex with ADC-7 β-lactamase, and all the crystal structures reveal the triazole is in the putative amide binding site, thus confirming the triazole-amide bioisosterism. The easy synthetic access of these new inhibitors as prototype scaffolds allows the insertion of a wide range of chemical groups able to explore the enzyme binding site and provides insights on the importance of specific residues in recognition and catalysis. The best inhibitor identified, compound ( 90 nM), places a tolyl group near Arg340, making favorable cation-π interactions. Notably, the structure of does not resemble the natural substrate of the β-lactamase yet displays a pronounced inhibition activity, in addition to lowering the minimum inhibitory concentration (MIC) of ceftazidime against three bacterial strains expressing class C β-lactamases. In summary, these observations validate the α-triazolylboronic acids as a promising template for further inhibitor design.

PubMed: 32502340
DOI: 10.1021/acsinfecdis.0c00254

Experimental method

X-RAY DIFFRACTION (1.96 Å)