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

David Yuxin Wang, Martine I Abboud, Marios S Markoulides, Jürgen Brem, Christopher J Schofield
2016 Future Medicinal Chemistry  
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, penicillinbinding protein and β-lactamase inhibitors. Like the β-lactam
more » ... e 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. Keywords : 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 For reprint orders, please contact Figure 3. Outline mechanisms of action of (A) serine and (B) metallo-β-lactamases. Note in the latter case one or two zinc ions may be present at the active site. Note that in each case the mechanism proceeds via a tetrahedral intermediate. Variations on the mechanisms shown can occur. (C) Active site view from a crystal structure of TEM-1 (cyan), a class A serine-β-lactamase, as acylated by penicillin G (pink) (PDB ID: 1FQG) [63]. (D) Active site view from a crystal structure of NDM-1 (cyan), a B1 metallo-β-lactamase, complexed with hydrolyzed penicillin G (pink) (PDB ID: 4EYF) [64].
doi:10.4155/fmc-2016-0078 pmid:27327972 fatcat:m234abbb4fektkwfds6cwhkmie