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 <i>Acinetobacter baumannii</i>

• Main Authors: Maria Luisa Introvigne (Author), Trevor J. Beardsley (Author), Micah C. Fernando (Author), David A. Leonard (Author), Bradley J. Wallar (Author), Susan D. Rudin (Author), Magdalena A. Taracila (Author), Philip N. Rather (Author), Jennifer M. Colquhoun (Author), Shaina Song (Author), Francesco Fini (Author), Kristine M. Hujer (Author), Andrea M. Hujer (Author), Fabio Prati (Author), Rachel A. Powers (Author), Robert A. Bonomo (Author), Emilia Caselli (Author)
• Format: Book
• Published: MDPI AG, 2023-03-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

<i>Acinetobacter baumannii</i> is a Gram-negative organism listed as an urgent threat pathogen by the World Health Organization (WHO). Carbapenem-resistant <i>A. baumannii</i> (CRAB), especially, present therapeutic challenges due to complex mechanisms of resistance to <i>β</i>-lactams. One of the most important mechanisms is the production of <i>β</i>-lactamase enzymes capable of hydrolyzing <i>β</i>-lactam antibiotics. Co-expression of multiple classes of <i>β</i>-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 <i>β</i>-lactamase inhibitors, we previously identified a sulfonamidomethaneboronic acid <b>CR167</b> active against <i>Acinetobacter</i>-derived class C <i>β</i>-lactamases (ADC-7). The compound demonstrated affinity for ADC-7 with a <i>K</i>_i = 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 <b>CR167</b> against other <i>β</i>-lactamases in <i>A. baumannii</i>: the cefepime-hydrolysing class C extended-spectrum <i>β</i>-lactamase (ESAC) ADC-33 and the carbapenem-hydrolyzing OXA-24/40 (class D). These investigations demonstrate <b>CR167</b> as a valuable cross-class (C and D) inhibitor, and the paper describes our attempts to further improve its activity. Five chiral analogues of <b>CR167</b> were rationally designed and synthesized. The structures of OXA-24/40 and ADC-33 in complex with <b>CR167</b> 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.

Item Description

10.3390/antibiotics12040644
2079-6382