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

What is it about?

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.

Featured Image

Why is it important?

Bacteria have evolved efficient mechanisms of resistance to β-lactam antibacterials, including by production of β-lactamases which catalyze β-lactam hydrolysis. Avibactam is a breakthrough because it is a broad-spectrum serine β-lactamase inhibitor, which is not itself a β-lactam; avibactam is approved for clinical use in combination with a cephalosporin (ceftazidime). Like the β-lactam class A serine β-lactamase and penicillin binding protein inhibitors and the lactivicins (the only naturally occurring small-molecule non-β-lactam penicillin-binding protein/serine β-lactamase inhibitors), avibactam has a core ring structure which enables inhibition via a mechanism involving covalent modification of a catalytically important nucleophilic serine residue. Unlike β-lactam inhibitors, which react irreversibly, avibactam reacts reversibly with its serine β-lactamase targets. The advent of avibactam should inspire further efforts to identify non-β-lactam penicillin-binding protein/serine β-lactamase inhibitors.