A new variant of the New Delhi metallo-enzyme (NDM) carbapenemase was identified in a multidrugresistant Escherichia coli ST648 isolate recovered from the perineum and throat of a patient in the United Kingdom with a recent history of hospitalization in India. NDM-5 differed from existing enzymes due to substitutions at positions 88 (Val3Leu) and 154 (Met3Leu) and reduced the susceptibility of E. coli TOP10 transformants to expanded-spectrum cephalosporins and carbapenems when expressed under its native promoter.

Infection due to Acinetobacter baumannii has become a significant challenge to modern healthcare systems. The organism shows a formidable capacity to develop antimicrobial resistance, yet the clinical impact of A. baumannii infection remains unclear. Much is known about the processes involved in multidrug resistance, but those underlying the pathogenicity and virulence potential of the organism are only beginning to be elucidated. In this article, we provide an overview of current knowledge, focusing on mechanisms of pathogenesis, the molecular basis of resistance and options for treatment in the absence of novel therapeutic agents.

Acquired carbapenemases pose one of the most pressing public health threats relating to antibiotic resistance. In most countries, the number of carbapenemase-producing bacteria from human clinical specimens is rising, and the epidemiological status of these multiresistant bacteria is progressively worsening. Furthermore, there is a growing number of reports of carbapenemases found either in bacteria isolated from non-human sources or in Salmonella enterica subsp. enterica, a zoonotic species. However, carbapenemases are not yet systematically sought in bacteria from non-human sources, reports of them are largely observational, and there is limited investigation of carbapenemase-positive bacteria in animals and possible links with people who may have acted as potential sources. Active surveillance and monitoring for carbapenem-resistant bacteria in the food chain and other non-human sources is urgently needed, with an enhanced and rigorous follow-up of all positive results. The carbapenems are currently our last good defence against multiresistant Gram-negative bacteria. Our ability to limit the rise and spread of carbapenemase producers, which occur only at basal levels in many countries at present, should serve as a key performance indicator for the success or failure of the efforts that have been called for by international organizations and governments to reduce the impact of antibiotic resistance.

ABSTRACTβ-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, and 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 catalyze their hydrolysis. To date, there are no clinically available metallo-β-lactamase inhibitors. Coproduction 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 this is 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-lactamases. 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-hydrolyzing 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.