Dataset Information

?-Lactamases and ?-Lactamase Inhibitors in the 21st Century.

ABSTRACT: The ?-lactams retain a central place in the antibacterial armamentarium. In Gram-negative bacteria, ?-lactamase enzymes that hydrolyze the amide bond of the four-membered ?-lactam ring are the primary resistance mechanism, with multiple enzymes disseminating on mobile genetic elements across opportunistic pathogens such as Enterobacteriaceae (e.g., Escherichia coli) and non-fermenting organisms (e.g., Pseudomonas aeruginosa). ?-Lactamases divide into four classes; the active-site serine ?-lactamases (classes A, C and D) and the zinc-dependent or metallo-?-lactamases (MBLs; class B). Here we review recent advances in mechanistic understanding of each class, focusing upon how growing numbers of crystal structures, in particular for ?-lactam complexes, and methods such as neutron diffraction and molecular simulations, have improved understanding of the biochemistry of ?-lactam breakdown. A second focus is ?-lactamase interactions with carbapenems, as carbapenem-resistant bacteria are of grave clinical concern and carbapenem-hydrolyzing enzymes such as KPC (class A) NDM (class B) and OXA-48 (class D) are proliferating worldwide. An overview is provided of the changing landscape of ?-lactamase inhibitors, exemplified by the introduction to the clinic of combinations of ?-lactams with diazabicyclooctanone and cyclic boronate serine ?-lactamase inhibitors, and of progress and strategies toward clinically useful MBL inhibitors. Despite the long history of ?-lactamase research, we contend that issues including continuing unresolved questions around mechanism; opportunities afforded by new technologies such as serial femtosecond crystallography; the need for new inhibitors, particularly for MBLs; the likely impact of new ?-lactam:inhibitor combinations and the continuing clinical importance of ?-lactams mean that this remains a rewarding research area.

SUBMITTER: Tooke CL

PROVIDER: S-EPMC6723624 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:There is no good science in bad models. Cell culture is especially prone to artifacts. A number of novel cell culture technologies have become more broadly available in the 21st century, which allow overcoming limitations of traditional culture and are more physiologically relevant. These include the use of stem-cell derived human cells, cocultures of different cell types, scaffolds and extracellular matrices, perfusion platforms (such as microfluidics), 3D culture, organ-on-chip technologies, tissue architecture, and organ functionality. The physiological relevance of such models is further enhanced by the measurement of biomarkers (e.g., key events of pathways), organ specific functionality, and more comprehensive assessment cell responses by high-content methods. These approaches are still rarely combined to create microphysiological systems. The complexity of the combination of these technologies can generate results closer to the in vivo situation but increases the number of parameters to control, bringing some new challenges. In fact, we do not argue that all cell culture needs to be that sophisticated. The efforts taken are determined by the purpose of our experiments and tests. If only a very specific molecular target to cell response is of interest, a very simple model, which reflects this, might be much more suited to allow standardization and high-throughput. However, the less defined the end point of interest and cellular response are, the better we should approximate organ- or tissue-like culture conditions to make physiological responses more probable. Besides these technologic advances, important progress in the quality assurance and reporting on cell cultures as well as the validation of cellular test systems brings the utility of cell cultures to a new level. The advancement and broader implementation of Good Cell Culture Practice (GCCP) is key here. In toxicology, this is a major prerequisite for meaningful and reliable results, ultimately supporting risk assessment and product development decisions.

Dataset Information

?-Lactamases and ?-Lactamase Inhibitors in the 21st Century.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets