The road to avibactam: the first clinically useful non-β-lactam working somewhat like a β-lactam.
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.
Department of Chemistry, University of Oxford, UK.
David Yuxin
DY
Wang
Department of Chemistry, University of Oxford, UK.
Martine I
MI
Abboud
Department of Chemistry, University of Oxford, UK.
Marios S
MS
Markoulides
Department of Chemistry, University of Oxford, UK.
Jürgen
J
Brem
Department of Chemistry, University of Oxford, UK.
Christopher J
CJ
Schofield
D000818:Animals; D053961:Azabicyclo Compounds / Q000737:chemistry / Q000494:pharmacology*; D001424:Bacterial Infections / Q000188:drug therapy / Q000382:microbiology; D006801:Humans; D065093:beta-Lactamase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D001618:beta-Lactamases / Q000378:metabolism*
D053961:Azabicyclo Compounds; D065093:beta-Lactamase Inhibitors; C543519:avibactam; D001618:beta-Lactamases
DBO; antibiotic resistance; avibactam; diazabicyclo[3.2.1]octane; lactivicin; metallo-β-lactamase; penicillin-binding protein; serine β-lactamase; β-lactam; β-lactamase inhibitor; γ-lactam