Synthesis of a Novel Boronic Acid Transition State Inhibitor, MB076: A Heterocyclic Triazole Effectively Inhibits Acinetobacter -Derived Cephalosporinase Variants with an Expanded-Substrate Spectrum.

Autor:	Powers RA; Department of Chemistry, Grand Valley State University, Allendale, Michigan 49401, United States., June CM; Department of Chemistry, Grand Valley State University, Allendale, Michigan 49401, United States., Fernando MC; Department of Chemistry, Grand Valley State University, Allendale, Michigan 49401, United States., Fish ER; Department of Chemistry, Grand Valley State University, Allendale, Michigan 49401, United States., Maurer OL; Department of Chemistry, Grand Valley State University, Allendale, Michigan 49401, United States., Baumann RM; Department of Chemistry, Grand Valley State University, Allendale, Michigan 49401, United States., Beardsley TJ; Department of Chemistry, Grand Valley State University, Allendale, Michigan 49401, United States., Taracila MA; Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, United States.; Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio 44106, United States., Rudin SD; Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, United States.; Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio 44106, United States., Hujer KM; Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, United States.; Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio 44106, United States., Hujer AM; Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, United States.; Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio 44106, United States., Santi N; Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 103, Modena 41125, Italy., Villamil V; Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 103, Modena 41125, Italy., Introvigne ML; Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 103, Modena 41125, Italy., Prati F; Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 103, Modena 41125, Italy., Caselli E; Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 103, Modena 41125, Italy., Bonomo RA; Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, United States.; Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio 44106, United States.; Pharmacology, Molecular Biology and Microbiology, Biochemistry, and Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, United States.; CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES), Cleveland, Ohio 44106, United States., Wallar BJ; Department of Chemistry, Grand Valley State University, Allendale, Michigan 49401, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2023 Jul 13; Vol. 66 (13), pp. 8510-8525. Date of Electronic Publication: 2023 Jun 26.
DOI:	10.1021/acs.jmedchem.3c00144
Abstrakt:	Class C Acinetobacter -derived cephalosporinases (ADCs) represent an important target for inhibition in the multidrug-resistant pathogen Acinetobacter baumannii . 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, MB076 , a novel heterocyclic triazole with improved plasma stability, was synthesized and inhibits seven different ADC β-lactamase variants with K i values <1 μM. MB076 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.
Databáze:	MEDLINE
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