The road to avibactam: The first clinically useful non-β-lactam working somewhat like a β-lactam

Journal article

Avibactam, which is the first non-β-lactam β-lactamase inhibitor to be introduced for clinical use, is a broad-spectrum serine β-lactamase inhibitor with activity against class A, class C, and, some, class D β-lactamases. We provide an overview of efforts, which extend to the period soon after the discovery of the penicillins, to develop clinically useful non-β-lactam compounds as antibacterials, and, subsequently, penicillin-binding protein and β-lactamase inhibitors. Like the β-lactam inhibitors, avibactam works via a mechanism involving covalent modification of a catalytically important nucleophilic serine residue. However, unlike the β-lactam inhibitors, avibactam reacts reversibly with its β-lactamase targets. We discuss chemical factors that may account for the apparently special nature of β-lactams and related compounds as antibacterials and β-lactamase inhibitors, including with respect to resistance. Avenues for future research including non-β-lactam antibacterials acting similarly to β-lactams are discussed.

Authors: Wang, D; Abboud, M; Markoulides, M; Brem, J; Schofield, C

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Future Science Ltd
• Journal: Future Medicinal Chemistry
• Volume: 8
• Issue: 10
• Pages: 1063-1084
• Publication date: 2016-06-01
• Acceptance date: 2016-05-06
• DOI: 10.4155/fmc-2016-0078
• EISSN: 1756-8927
• ISSN: 1756-8919
• Language: English
• Keywords: metallo-β-lactamase; serine β-lactamase; DBO; antibiotic resistance; lactivicin; avibactam; β-lactamase inhibitor; β-lactam; Journal Article; γ-lactam; diazabicyclo[3.2.1]octane; penicillin-binding protein