Studies on enmetazobactam clarify mechanisms of widely used β-lactamase inhibitors

Lang, Pauline A.; Raj, Ritu; Tumber, Anthony; Lohans, Christopher T.; Rabe, Patrick; Robinson, Carol V.; Brem, Jürgen; Schofield, Christopher J.

doi:10.1073/pnas.2117310119

Cited by 6 publications

(4 citation statements)

References 70 publications

(152 reference statements)

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“…BLIs target β-lactamases to prevent β-lactam hydrolysis, therefore keeping the antibiotic intact and capable of acting on PBPs. FDA-approved BLIs include the classical inhibitors clavulanic acid, tazobactam, and sul-bactam, and the relatively new compounds avibactam and vaborbactam, all of which are designed to be used in combination with a respective β-lactam [22][23][24]. Unfortunately, resistance to β-lactam-BLI combinations has been identified both in the laboratory and clinical settings, including against avibactam and vaborbactam, even before their approval by the FDA [25][26][27].…”

Section: Targeting β-Lactamases: Innovative Technologies and Promisin...mentioning

confidence: 99%

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

Jacobs,

Consol,

Chen

2024

Antibiotics

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β-Lactams are the most widely prescribed class of antibiotics that inhibit penicillin-binding proteins (PBPs), particularly transpeptidases that function in peptidoglycan synthesis. A major mechanism of antibiotic resistance is the production of β-lactamase enzymes, which are capable of hydrolyzing β-lactam antibiotics. There have been many efforts to counter increasing bacterial resistance against β-lactams. These studies have mainly focused on three areas: discovering novel inhibitors against β-lactamases, developing new β-lactams less susceptible to existing resistance mechanisms, and identifying non-β-lactam inhibitors against cell wall transpeptidases. Drug discovery in the β-lactam field has afforded a range of research opportunities for academia. In this review, we summarize the recent new findings on both β-lactamases and cell wall transpeptidases because these two groups of enzymes are evolutionarily and functionally connected. Many efforts to develop new β-lactams have aimed to inhibit both transpeptidases and β-lactamases, while several promising novel β-lactamase inhibitors have shown the potential to be further developed into transpeptidase inhibitors. In addition, the drug discovery progress against each group of enzymes is presented in three aspects: understanding the targets, screening methodology, and new inhibitor chemotypes. This is to offer insights into not only the advancement in this field but also the challenges, opportunities, and resources for future research. In particular, cyclic boronate compounds are now capable of inhibiting all classes of β-lactamases, while the diazabicyclooctane (DBO) series of small molecules has led to not only new β-lactamase inhibitors but potentially a new class of antibiotics by directly targeting PBPs. With the cautiously optimistic successes of a number of new β-lactamase inhibitor chemotypes and many questions remaining to be answered about the structure and function of cell wall transpeptidases, non-β-lactam transpeptidase inhibitors may usher in the next exciting phase of drug discovery in this field.

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Section: Targeting β-Lactamases: Innovative Technologies and Promisin...mentioning

confidence: 99%

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

Jacobs,

Consol,

Chen

2024

Antibiotics

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“…Enmetazobactam, an N-methylated derivative of tazobactam, is known to inhibit members of all serine β-lactamase classes without major structural shattering ( Lang et al, 2022 ). Enmetazobactam is a penicillin-derived sulfone specifically known to inhibit Enterobacterales -producing class C and D carbapenemases ( Crandon and Nicolau, 2015 ; Morrissey et al, 2019 ).…”

Section: Enmetazobactammentioning

confidence: 99%

“…It inhibits serine β-lactamase and its production in bacterial species. Enmetazobactam is known to cause irreversible inhibition ( Lang et al, 2022 ).…”

Section: Enmetazobactammentioning

confidence: 99%

Biochemical exploration of β-lactamase inhibitors

Arer

Kar

2023

Front. Genet.

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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.

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“…S2 and S10, ESI †). [36][37][38] Interestingly, the ortho-trifluoromethoxy substituents on the phenyl groups of 5 promoted Dha formation (B30% in 24 h). Dha formation was additionally observed following reaction with 4 (B2.5% in 24 h) and 7 (B16% in 24 h).…”

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confidence: 99%