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

is a Gram-negative organism listed as an urgent threat pathogen by the World Health Organization (WHO). Carbapenem-resistant (CRAB), especially, present therapeutic challenges due to complex mechanisms of resistance to -lactams. One of the most important mechanisms is the production of -lactamase enzymes capable of hydrolyzing -lactam antibiotics. Co-expression of multiple classes of -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 -lactamase inhibitors, we previously identified a sulfonamidomethaneboronic acid active against -derived class C -lactamases (ADC-7). The compound demonstrated affinity for ADC-7 with a = 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 against other -lactamases in : the cefepime-hydrolysing class C extended-spectrum -lactamase (ESAC) ADC-33 and the carbapenem-hydrolyzing OXA-24/40 (class D). These investigations demonstrate as a valuable cross-class (C and D) inhibitor, and the paper describes our attempts to further improve its activity. Five chiral analogues of were rationally designed and synthesized. The structures of OXA-24/40 and ADC-33 in complex with 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.