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

• Type of Material: Article
• 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
• Language: English
• Date: 2023-04-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2023 by the authors. Licensee MDPI, Basel, Switzerland.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/antibiotics12040644
• Title of Journal or Parent Work: ANTIBIOTICS-BASEL
• Volume: 12
• Issue: 4
• Grant/Funding Information: Research reported in this publication was supported by a grant from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH) to R.A.B. under Award Number R01AI072219. This study was also partially supported by funds provided by the Ministry of University and Research of Italy and the Department of Life Science to E.C. (FFABR N° E51I17000650005) and F.F. (FAR-DSV 2021, FAR-DSV 2019) and by funds and/or facilities provided by the Cleveland Department of Veterans Affairs, Award Number 1I01BX001974, to R.A.B. from the Biomedical Laboratory Research and Development Service of the VA Office of Research and Development and the Geriatric Research Education and Clinical Center VISN 10. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the Department of Veterans Affairs. This research used the resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract no. DE-AC02-06CH11357. Use of the LS-CAT Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor (grant 085P1000817). JMC was supported by a career development award (IK2BX005911) from the Department of Veterans Affairs. PNR is supported by Department of Veterans Affairs awards I01 BX001725 and IK6BX004470.
• Keywords: Pharmacology & Pharmacy; beta-lactamases; Life Sciences & Biomedicine; Infectious Diseases; BORONIC ACIDS; STRUCTURAL BASIS; BETA-LACTAMASE INHIBITOR; CLASS-A; DISCOVERY; antibiotic resistance; Science & Technology; Acinetobacter baumannii; cross-class inhibitors; boronic acids

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.