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 Acinetobacter baumannii

• Authors: Maria Luisa Introvigne, Univ Modena & Reggio Emilia; Trevor J Beardsley, Grand Valley State University; Michah CC Fernando, Grand Valley State University; David AA Leonard, Grand Valley State University; Bradley J Wallar, Grand Valley State University; Susan D Rudin, Case Western Reserve Univ Sch Med; Magdalena A Taracila, Case Western Reserve Univ Sch Med; Philip Rather, Emory University; Jennifer M Colquhoun, Emory University; Shaina Song, Atlanta Veterans Medical Center, Decatur; Francesco Fini, Università di Modena e Reggio Emilia; Kristine M Hujer, Case Western Reserve Univ Sch Med; Andrea M Hujer, Case Western Reserve Univ Sch Med; Fabio Prati, Università di Modena e Reggio Emilia, Via Campi 103; Rachel A Powers, Grand Valley State University; Robert A Bonomo, Case Western Reserve Univ Sch Med; Emilia Caselli, Università di Modena e Reggio Emilia
• Journal Title: ANTIBIOTICS-BASEL
• Volume: Volume 12, Number 4
• Publisher: MDPI | 2023-04-01
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.3390/antibiotics12040644
• Subjects: Biology, Microbiology; Health Sciences, Immunology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Infectious Diseases; Pharmacology & Pharmacy; antibiotic resistance; beta-lactamases; Acinetobacter baumannii; boronic acids; cross-class inhibitors; BETA-LACTAMASE INHIBITOR; BORONIC ACIDS; CLASS-A; STRUCTURAL BASIS; DISCOVERY

Abstract

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.