8FQR

Apo ADC-212 beta-lactamase

Summary for 8FQR

• Entry DOI: 10.2210/pdb8fqr/pdb
• Descriptor: Beta-lactamase, GLYCINE, PHOSPHATE ION, ... (4 entities in total)
• Functional Keywords: acinetobacter-derived cephalosporinase, hydrolase
• Biological source: Acinetobacter baumannii
• Total number of polymer chains: 1
• Total formula weight: 40984.57

Authors

Powers, R.A.,Wallar, B.J.,June, C.M.,Beardsley, T.J. (deposition date: 2023-01-06, release date: 2023-07-05, Last modification date: 2023-10-25)

Primary citation

Powers, R.A.,June, C.M.,Fernando, M.C.,Fish, E.R.,Maurer, O.L.,Baumann, R.M.,Beardsley, T.J.,Taracila, M.A.,Rudin, S.D.,Hujer, K.M.,Hujer, A.M.,Santi, N.,Villamil, V.,Introvigne, M.L.,Prati, F.,Caselli, E.,Bonomo, R.A.,Wallar, B.J.
Synthesis of a Novel Boronic Acid Transition State Inhibitor, MB076: A Heterocyclic Triazole Effectively Inhibits Acinetobacter -Derived Cephalosporinase Variants with an Expanded-Substrate Spectrum.
J.Med.Chem., 66:8510-8525, 2023

PubMed Abstract: Class C -derived cephalosporinases (ADCs) represent an important target for inhibition in the multidrug-resistant pathogen . Many ADC variants have emerged, and characterization of their structural and functional differences is essential. Equally as important is the development of compounds that inhibit all prevalent ADCs despite these differences. The boronic acid transition state inhibitor, , a novel heterocyclic triazole with improved plasma stability, was synthesized and inhibits seven different ADC β-lactamase variants with values <1 μM. acted synergistically in combination with multiple cephalosporins to restore susceptibility. ADC variants containing an alanine duplication in the Ω-loop, specifically ADC-33, exhibited increased activity for larger cephalosporins, such as ceftazidime, cefiderocol, and ceftolozane. X-ray crystal structures of ADC variants in this study provide a structural context for substrate profile differences and show that the inhibitor adopts a similar conformation in all ADC variants, despite small changes near their active sites.

PubMed: 37358467
DOI: 10.1021/acs.jmedchem.3c00144

Experimental method

X-RAY DIFFRACTION (1.24 Å)