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

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