Biochemical exploration of β-lactamase inhibitors

Abstract

The alarming rise of microbial resistance to antibiotics has severely limited the efficacy of current treatment options. The prevalence of β-lactamase enzymes is a significant contributor to the emergence of antibiotic resistance. There are four classes of β-lactamases: A, B, C, and D. Class B is the metallo-β-lactamase, while the rest are serine β-lactamases. The clinical use of β-lactamase inhibitors began as an attempt to combat β-lactamase-mediated resistance. Although β-lactamase inhibitors alone are ineffective against bacteria, research has shown that combining inhibitors with antibiotics is a safe and effective treatment that not only prevents β-lactamase formation but also broadens the range of activity. These inhibitors may cause either temporary or permanent inhibition. The development of new β-lactamase inhibitors will be a primary focus of future research. This study discusses recent advances in our knowledge of the biochemistry behind β-lactam breakdown, with special emphasis on the mechanism of inhibitors for β-lactam complexes with β-lactamase. The study also focuses on the pharmacokinetic and pharmacodynamic properties of all inhibitors and then applies them in clinical settings. Our analysis and discussion of the challenges that exist in designing inhibitors might help pharmaceutical researchers address root issues and develop more effective inhibitors.

Exploiting the Carboxylate-Binding Pocket of β-Lactamase Enzymes Using a Focused DNA-Encoded Chemical Library

“…Existing inhibitors and those currently in clinical trials utilize a covalent handle in the form of a β-lactam, DBO, or boronate. 13,14,17 Although the development of inhibitors for all classes of β-lactamase enzymes is an active area of research, bacteria are evolving to develop resistance against the newer inhibitors. 15,16,41−43 DECL-based drug discovery is a powerful method to discover novel noncovalent inhibitors that are structurally different from current antibiotics.…”

“…This validates the premise of the focused library targeting the carboxylatebinding pocket and the importance of the carboxylic acid for inhibition of the NDM-1 enzyme. Because a free amine has been reported to enhance the accumulation of compounds into bacteria, 40 we converted the methylamine on P1 to a free amine (13). This resulted in a 2.5-fold loss in potency.…”

“…Molecular formula: C 20 H 20 N 2 O 4 ; 1 H NMR (600 MHz, DMSO) δ 8.73 (s, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.13 (t, J = 7.8 Hz, 1H), 692− 6.87 (m, 2H), 6.79−6.75 (m, 2H), 6.75−6.71 (m, 1H), 6.63 (d, J = 7.4 Hz, 1H), 6.39−6.33 (m, 2H), 4.31 (d, J = 5.9 Hz, 2H), 3.97 (s, 2H), 2.54 (s, 3H). 13…”

“…Molecular formula: C 19 H 18 N 2 O 4 ; 1 H NMR (600 MHz, MeOD) δ 7.82 (d, J = 7.7 Hz, 1H), 7.20 (t, J = 7.8 Hz, 1H), 7.11 (s, 2H), 6.81− 6.78 (m, 1H), 6.77 (s, 1H), 6.75 (d, J = 3.0 Hz, 1H), 6.69 (d, J = 7.3 Hz, 1H), 6.35 (d, J = 2.8 Hz, 1H), 4.41 (s, 2H), 3.99 (s, 2H). 13…”

“…Chemical formula: C 20 H 19 N 3 O 3 ; 1 H NMR (600 MHz, DMSO) δ 8.54 (d, J = 5.2 Hz, 1H), 7.99 (bs, 3H), 7.73 (d, J = 7.9 Hz, 1H), 7.61 (s, 1H), 7.52 (dd, J = 5.2, 1.6 Hz, 1H), 7.09 (t, J = 7.8 Hz, 1H), 6.93 (d, J = 1.7 Hz, 1H), 6.91 (dd, J = 7.9, 1.8 Hz, 1H), 6.72 (s, 1H), 6.62−6.59 (m, 2H), 6.55 (s, 1H), 4.42 (d, J = 6.2 Hz, 2H), 3.87 (s, 2H), 3.17 (d, J = 2.3 Hz, 1H). 13 Final Product. General experimental procedure D was followed with TFA, followed by general experimental procedure E.…”