Will morphing boron-based inhibitors beat the β-lactamases?. (June 2019)

• Record Type: Journal Article
• Authors: Krajnc, Alen; Lang, Pauline A; Panduwawala, Tharindi D; Brem, Jürgen; Schofield, Christopher J
• Is Part Of: Current opinion in chemical biology. Volume 50(2019)
• Page Start: 101
• Page End: 110
• Publication Date: 2019-06
• Subjects: Bioorganic chemistry -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Clinical biochemistry -- Periodicals; Biochemistry -- Periodicals; Chimie bio-organique -- Périodiques; Biologie -- Périodiques; 572.05
• DOI: 10.1016/j.cbpa.2019.03.001
• Languages: English
• ISSNs: 1367-5931

Abstract

Abstract : The β-lactams remain the most important antibacterials, but their use is increasingly compromised by resistance, importantly by β-lactamases. Although β-lactam and non-β-lactam inhibitors forming stable acyl–enzyme complexes with nucleophilic serine β-lactamases (SBLs) are widely used, these are increasingly susceptible to evolved SBLs and do not inhibit metallo-β-lactamases (MBLs). Boronic acids and boronate esters, especially cyclic ones, can potently inhibit both SBLs and MBLs. Vaborbactam, a monocyclic boronate, is approved for clinical use, but its β-lactamase coverage is limited. Bicyclic boronates rapidly react with SBLs and MBLs forming stable enzyme–inhibitor complexes that mimic the common anionic high-energy tetrahedral intermediates in SBL/MBL catalysis, as revealed by crystallography. The ability of boronic acids to 'morph' between sp 2 and sp 3 hybridisation states may help enable potent inhibition. There is limited structure–activity relationship information on the (bi)cyclic boronate inhibitors compared to β-lactams, hence scope for creativity towards new boron-based β-lactamase inhibitors/antibacterials.