Sulfonamidoboronic Acids as “Cross-Class” Inhibitors of an Expanded-Spectrum Class C Cephalosporinase, ADC-33, and a Class D Carbapenemase, OXA-24/40: Strategic Compound Design to Combat Resistance in <i>Acinetobacter baumannii</i>
Maria Luisa Introvigne,
Trevor J. Beardsley,
Micah C. Fernando,
David A. Leonard,
Bradley J. Wallar,
Susan D. Rudin,
Magdalena A. Taracila,
Philip N. Rather,
Jennifer M. Colquhoun,
Shaina Song,
Francesco Fini,
Kristine M. Hujer,
Andrea M. Hujer,
Fabio Prati,
Rachel A. Powers,
Robert A. Bonomo,
Emilia Caselli
Affiliations
Maria Luisa Introvigne
Department of Life Sciences, Università di Modena e Reggio Emilia, Via Campi 103, 41125 Modena, Italy
Trevor J. Beardsley
Department of Chemistry, Grand Valley State University, Allendale, MI 49401, USA
Micah C. Fernando
Department of Chemistry, Grand Valley State University, Allendale, MI 49401, USA
David A. Leonard
Department of Chemistry, Grand Valley State University, Allendale, MI 49401, USA
Bradley J. Wallar
Department of Chemistry, Grand Valley State University, Allendale, MI 49401, USA
Susan D. Rudin
Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
Magdalena A. Taracila
Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
Philip N. Rather
Research Service, Atlanta Veterans Medical Center, Decatur, GA 30033, USA
Jennifer M. Colquhoun
Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30307, USA
Shaina Song
Research Service, Atlanta Veterans Medical Center, Decatur, GA 30033, USA
Francesco Fini
Department of Life Sciences, Università di Modena e Reggio Emilia, Via Campi 103, 41125 Modena, Italy
Kristine M. Hujer
Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
Andrea M. Hujer
Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
Fabio Prati
Department of Life Sciences, Università di Modena e Reggio Emilia, Via Campi 103, 41125 Modena, Italy
Rachel A. Powers
Department of Chemistry, Grand Valley State University, Allendale, MI 49401, USA
Robert A. Bonomo
Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
Emilia Caselli
Department of Life Sciences, Università di Modena e Reggio Emilia, Via Campi 103, 41125 Modena, Italy
Acinetobacter baumannii is a Gram-negative organism listed as an urgent threat pathogen by the World Health Organization (WHO). Carbapenem-resistant A. baumannii (CRAB), especially, present therapeutic challenges due to complex mechanisms of resistance to β-lactams. One of the most important mechanisms is the production of β-lactamase enzymes capable of hydrolyzing β-lactam antibiotics. Co-expression of multiple classes of β-lactamases is present in CRAB; therefore, the design and synthesis of “cross-class” inhibitors is an important strategy to preserve the efficacy of currently available antibiotics. To identify new, nonclassical β-lactamase inhibitors, we previously identified a sulfonamidomethaneboronic acid CR167 active against Acinetobacter-derived class C β-lactamases (ADC-7). The compound demonstrated affinity for ADC-7 with a Ki = 160 nM and proved to be able to decrease MIC values of ceftazidime and cefotaxime in different bacterial strains. Herein, we describe the activity of CR167 against other β-lactamases in A. baumannii: the cefepime-hydrolysing class C extended-spectrum β-lactamase (ESAC) ADC-33 and the carbapenem-hydrolyzing OXA-24/40 (class D). These investigations demonstrate CR167 as a valuable cross-class (C and D) inhibitor, and the paper describes our attempts to further improve its activity. Five chiral analogues of CR167 were rationally designed and synthesized. The structures of OXA-24/40 and ADC-33 in complex with CR167 and select chiral analogues were obtained. The structure activity relationships (SARs) are highlighted, offering insights into the main determinants for cross-class C/D inhibitors and impetus for novel drug design.
