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

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.

Drug Discovery in the Field of β-Lactams: An Academic Perspective

“…These novel inhibitor chemotypes have led to new combination therapies targeting β-lactam resistance and a better understanding of β-lactamase activity. (1 [105], 2 [106], 3 [107], 4 [108], Ixazomib [109], 5 [110], 6 [111], 7 [112], ZINC549719643 [89], 8 [113], 9 [114], 10 [115], 11 [116], 12 [117], 13 [118], 14 [119], 15 [120], 16 [121], QPX7728 [122,123], 17 [124], 18 [125], 19 [126], 20 [127]).…”

“…Compound 2 had a K i of 0.032 µM and an MIC of < 0.06 µg/mL, which can act as a guide for a new class of boronic acid inhibitors. In another study, boronic acid inhibitors were developed to target class D enzymes while retaining activity toward class C [107]. The benzyl sulfonamide derivative 3 has a K i of 4.4 µM against OXA-24/40 and 0.057 µM against ADC-33.…”

“…The compound name in the original publication is provided in parenthesis. (1[105], 2[106], 3[107], 4[108], Ixazomib[109], 5[110], 6[111], 7[112], ZINC549719643[89], 8[113], 9[114], 10[115], 11[116], 12[117], 13[118], 14[119], 15[120], 16[121], QPX7728[122,123], 17[124], 18[125], 19[126], 20[127]).…”