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Carbapenem-resistant A. baumannii (CRAB), especially, present therapeutic challenges due to complex mechanisms of resistance to \u03b2-lactams. One of the most important mechanisms is the production of \u03b2-lactamase enzymes capable of hydrolyzing \u03b2-lactam antibiotics. Co-expression of multiple classes of \u03b2-lactamases is present in CRAB; therefore, the design and synthesis of \u201ccross-class\u201d inhibitors is an important strategy to preserve the efficacy of currently available antibiotics. To identify new, nonclassical \u03b2-lactamase inhibitors, we previously identified a sulfonamidomethaneboronic acid CR167 active against Acinetobacter-derived class C \u03b2-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 \u03b2-lactamases in A. baumannii: the cefepime-hydrolysing class C extended-spectrum \u03b2-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.<\/jats:p>","DOI":"10.3390\/antibiotics12040644","type":"journal-article","created":{"date-parts":[[2023,3,24]],"date-time":"2023-03-24T03:50:21Z","timestamp":1679629821000},"page":"644","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Sulfonamidoboronic Acids as \u201cCross-Class\u201d 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"],"prefix":"10.3390","volume":"12","author":[{"given":"Maria Luisa","family":"Introvigne","sequence":"first","affiliation":[{"name":"Department of Life Sciences, Universit\u00e0 di Modena e Reggio Emilia, Via Campi 103, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trevor J.","family":"Beardsley","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Grand Valley State University, Allendale, MI 49401, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micah C.","family":"Fernando","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Grand Valley State University, Allendale, MI 49401, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Leonard","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Grand Valley State University, Allendale, MI 49401, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley J.","family":"Wallar","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Grand Valley State University, Allendale, MI 49401, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan D.","family":"Rudin","sequence":"additional","affiliation":[{"name":"Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA"},{"name":"Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena A.","family":"Taracila","sequence":"additional","affiliation":[{"name":"Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA"},{"name":"Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip N.","family":"Rather","sequence":"additional","affiliation":[{"name":"Research Service, Atlanta Veterans Medical Center, Decatur, GA 30033, USA"},{"name":"Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30307, USA"},{"name":"Emory Antibiotic Resistance Center, Emory University School of Medicine, Atlanta, GA 30307, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer M.","family":"Colquhoun","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30307, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaina","family":"Song","sequence":"additional","affiliation":[{"name":"Research Service, Atlanta Veterans Medical Center, Decatur, GA 30033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2555-9313","authenticated-orcid":false,"given":"Francesco","family":"Fini","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Universit\u00e0 di Modena e Reggio Emilia, Via Campi 103, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristine M.","family":"Hujer","sequence":"additional","affiliation":[{"name":"Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA"},{"name":"Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea M.","family":"Hujer","sequence":"additional","affiliation":[{"name":"Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA"},{"name":"Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Prati","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Universit\u00e0 di Modena e Reggio Emilia, Via Campi 103, 41125 Modena, 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USA"},{"name":"CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES), Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7248-9453","authenticated-orcid":false,"given":"Emilia","family":"Caselli","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Universit\u00e0 di Modena e Reggio Emilia, Via Campi 103, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1007\/s11756-021-00697-x","article-title":"Antibiotic Resistance Crisis: Challenges and Imperatives","volume":"76","author":"Church","year":"2021","journal-title":"Biologia"},{"key":"ref_2","unstructured":"(2023, January 31). 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