Cyclic Boronates Inhibit All Classes of β-Lactamase

β-Lactamase-mediated resistance is a growing threat to the continued use of β-lactam antibiotics. The use of the β-lactam-based serine-β-lactamase (SBL) inhibitors clavulanic acid, sulbactam, tazobactam, and, more recently, the non-β-lactam inhibitor avibactam has extended the utility of β-lactams against bacterial infections demonstrating resistance via these enzymes. These molecules are, however, ineffective against the metallo-β-lactamases (MBLs), which catalyse their hydrolysis. To date, there are no clinically available metallo-β-lactamase inhibitors. Co-production of MBLs and SBLs in resistant infections is, thus, of major clinical concern. The development of ‘dual-action' inhibitors, targeting both SBLs and MBLs, is of interest, but these are considered difficult to achieve due to the structural and mechanistic differences between the two enzyme classes. We recently reported evidence that cyclic boronates can inhibit both serine- and metallo-β-lactmases. Here we report that cyclic boronates are able to inhibit all four classes of β-lactamase, including the class A extended spectrum β-lactamase, CTX-M-15, the class C enzyme, AmpC from Pseudomonas aeruginosa, and class D OXA enzymes with carbapenem-hydrolysing capabilities. We demonstrate that cyclic boronates can potentiate the use of β-lactams against Gram-negative clinical isolates expressing a variety of β-lactamases. Comparison of a crystal structure of a CTX-M-15:cyclic boronate complex with structures of cyclic boronates complexed with other β-lactamases reveals remarkable conservation of the small molecule binding mode, supporting our proposal that these molecules work by mimicking the common tetrahedral anionic intermediate present in both serine- and metallo-β-lactamase catalysis

Domesticating the ‘troubled family’: Racialised sexuality and the postcolonial governance of family life in the UK

This article examines how the UK’s Troubled Families Programme (TFP) works as a strategy of domestication which produces and delimits certain forms of ‘family life’. Drawing upon critical geographies of home and empire, the article explores how the TFP works to manage the troubled family as part of a longer history of regulating unruly households in the name of national health and civilisation. Viewing the TFP as part of the production of heteronormative order, highlights how the policy remobilises and reconfigures older forms of colonial rule which work to demarcate between civility/savagery, the developable/undevelopable. In examining the postcolonial dimension of neoliberal social policy, the article stresses how the TFP relies on racializing and sexualised logics of socio-biological control borrowed from imperial eugenics. Reading the TFP in this way contributes to our understanding of neoliberal rule. That the troubled family can be either domesticated or destroyed (through benefit sanctions and eviction) equally reveals the extent to which domesticity works as a key site for the production of both ‘worthy’ and ‘surplus’ life

Critical geographies and the uses of sexuality: Deconstructing queer space

10.1177/0309132507085213Progress in Human Geography32189-10