The road to avibactam: the first clinically useful non-β-lactam working somewhat like a β-lactam. (June 2016)

• Record Type: Journal Article
• Authors: Wang, David Yuxin; Abboud, Martine I; Markoulides, Marios S; Brem, Jürgen; Schofield, Christopher J
• Is Part Of: Future medicinal chemistry. Volume 8:Number 10(2016)
• Page Start: 1063
• Page End: 1084
• Publication Date: 2016-06
• Subjects: β-lactamase inhibitor -- β-lactam -- γ-lactam -- antibiotic resistance -- avibactam -- DBO -- diazabicyclo[3.2.1]octane -- lactivicin -- metallo-β-lactamase -- penicillin-binding protein -- serine β-lactamase; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.4155/fmc-2016-0078
• Languages: English
• ISSNs: 1756-8919

Abstract

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.