ORCID Profile
0000-0002-4439-7738
Current Organisation
University of Oxford
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Publisher: Springer Science and Business Media LLC
Date: 30-07-2020
DOI: 10.1038/S41598-020-68612-Z
Abstract: Genes that confer antibiotic resistance can rapidly be disseminated from one microorganism to another by mobile genetic elements, thus transferring resistance to previously susceptible bacterial strains. The misuse of antibiotics in health care and agriculture has provided a powerful evolutionary pressure to accelerate the spread of resistance genes, including those encoding β-lactamases. These are enzymes that are highly efficient in inactivating most of the commonly used β-lactam antibiotics. However, genes that confer antibiotic resistance are not only associated with pathogenic microorganisms, but are also found in non-pathogenic (i.e. environmental) microorganisms. Two recent ex les are metal-dependent β-lactamases (MBLs) from the marine organisms Novosphingobium pentaromativorans and Simiduia agarivorans. Previous studies have demonstrated that their β-lactamase activity is comparable to those of well-known MBLs from pathogenic sources (e.g. NDM-1, AIM-1) but that they also possess efficient lactonase activity, an activity associated with quorum sensing. Here, we probed the structure and mechanism of these two enzymes using crystallographic, spectroscopic and fast kinetics techniques. Despite highly conserved active sites both enzymes demonstrate significant variations in their reaction mechanisms, highlighting both the extraordinary ability of MBLs to adapt to changing environmental conditions and the rather promiscuous acceptance of erse substrates by these enzymes.
Publisher: Cold Spring Harbor Laboratory
Date: 16-08-2019
DOI: 10.1101/737403
Abstract: Antibiotic resistance has emerged as a major global health threat. The Zn 2+ -dependent metallo-β-lactamases (MBLs) are of particular concern as they act on the most widely prescribed class of antibiotics, the β-lactams, and are largely unaffected by commonly used β-lactamase antagonists such as clavulanic acid. MBLs are sub ided into three groups (B1 to B3) despite low overall sequence similarity, their catalytic centers are conserved with two closely spaced Zn 2+ binding sites (α and β site). We recovered almost 1500 B3 MBLs from ,000 public microbial genomes representing a wide range of habitats including pristine sites not impacted by human activity. Although homologs were predominantly identified in members of the bacterial phylum Proteobacteria , the recovered B3 MBLs represent a much broader phylogenetic ersity than is currently appreciated based on the study of model pathogens. This includes three active site variants inferred to have arisen from the ancestral B3 enzyme. One of these variants, B3-RQK, is noteworthy for being broadly sensitive to clavulanic acid. Through targeted mutations we demonstrate that the presence of a lysine residue (Lys263) in the β site of the catalytic center of this variant confers sensitivity to this compound. Replacing this lysine with the canonical histidine (His263) found in all other MBLs restored resistance. Crystallographic and computational data reveal that clavulanic acid inhibits B3-RQK MBLs by displacing the Zn 2+ ion in the β site. Therefore, modifying clavulanic acid to effectively interact with His263 may increase the therapeutic range of this widely used antibiotic resistance drug. This study surveys the environmental and phylogenetic ersity of the B3 subgroup of antibiotic-degrading metallo-β-lactamases (MBLs). B3-like MBLs are more widespread in the environment than previously appreciated suggesting multiple unrecognized reservoirs of antibiotic resistance. Three variants of the canonical active site were identified, including B3-RQK, which amongst the B3 MBLs is uniquely inhibited by the antibiotic resistance drug clavulanic acid. We demonstrate that the mode of inhibition involves the displacement of a catalytically essential Zn 2+ ion from the active site. It may thus be possible to modify clavulanic acid so that it can compete with the Zn 2+ ions in other MBLs as well, increasing the therapeutic range of this compound.
Publisher: Frontiers Media SA
Date: 20-06-2023
DOI: 10.3389/FCHEM.2023.1196073
Abstract: β-Lactams are the most widely employed antibiotics in clinical settings due to their broad efficacy and low toxicity. However, since their first use in the 1940s, resistance to β-lactams has proliferated to the point where multi-drug resistant organisms are now one of the greatest threats to global human health. Many bacteria use β-lactamases to inactivate this class of antibiotics via hydrolysis. Although nucleophilic serine-β-lactamases have long been clinically important, most broad-spectrum β-lactamases employ one or two metal ions (likely Zn 2+ ) in catalysis. To date, potent and clinically useful inhibitors of these metallo-β-lactamases (MBLs) have not been available, exacerbating their negative impact on healthcare. MBLs are categorised into three subgroups: B1, B2, and B3 MBLs, depending on their sequence similarities, active site structures, interactions with metal ions, and substrate preferences. The majority of MBLs associated with the spread of antibiotic resistance belong to the B1 subgroup. Most characterized B3 MBLs have been discovered in environmental bacteria, but they are increasingly identified in clinical s les. B3-type MBLs display greater ersity in their active sites than other MBLs. Furthermore, at least one of the known B3-type MBLs is inhibited by the serine-β-lactamase inhibitor clavulanic acid, an observation that may promote the design of derivatives active against a broader range of MBLs. In this Mini Review, recent advances in structure-function relationships of B3-type MBLs will be discussed, with a view to inspiring inhibitor development to combat the growing spread of β-lactam resistance.
Publisher: Elsevier BV
Date: 04-2020
Publisher: Elsevier BV
Date: 2017
DOI: 10.1016/J.JINORGBIO.2016.11.015
Abstract: Agmatine (1-amino-4-guanidinobutane) plays an important role in a range of metabolic functions, in particular in the brain. Agmatinases (AGMs) are enzymes capable of converting agmatine to the polyamine putrescine and urea. AGMs belong to the family of Mn
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1016/J.JINORGBIO.2016.11.028
Abstract: Alternative solutions need to be developed to overcome the growing problem of multi-drug resistant bacteria. This study explored the possibility of creating complexes of antibiotics with metal ions, thereby increasing their activity. Analytical techniques such as isothermal titration calorimetry and nuclear magnetic resonance were used to examine the structure and interactions between Cu(II), Ag(I) or Zn(II) and β-lactam antibiotics. The metal-β-lactam complexes were also tested for antimicrobial activity, by micro-broth dilution and disk diffusion methods, showing a synergistic increase in the activity of the drugs, and enzymatic inhibition assays confirming inhibition of β-lactamases responsible for resistance. The metal-antibiotic complex concept was proven to be successful with the activity of the drugs enhanced against β-lactamase-producing bacteria. The highest synergistic effects were observed for complexes formed with Ag(I).
Publisher: American Society for Microbiology
Date: 17-09-2021
DOI: 10.1128/AAC.00936-21
Abstract: The structural ersity in metallo-β-lactamases (MBLs), especially in the vicinity of the active site, has been a major hurdle in the development of clinically effective inhibitors. Representatives from three variants of the B3 MBL subclass, containing either the canonical HHH/DHH active-site motif (present in the majority of MBLs in this subclass) or the QHH/DHH (B3-Q) or HRH/DQK (B3-RQK) variations were reported previously.
Publisher: Elsevier BV
Date: 2023
DOI: 10.1016/J.JINORGBIO.2022.112061
Abstract: Biomimetics hold potential for varied applications in biotechnology and medicine but have also attracted particular interest as benchmarks for the functional study of their more complex biological counterparts, e.g. metalloenzymes. While many of the synthetic systems adequately mimic some structural and functional aspects of their biological counterparts the catalytic efficiencies displayed are mostly far inferior due to the smaller size and the associated lower complexity. Nonetheless they play an important role in bioinorganic chemistry. Numerous ex les of biologically inspired and informed artificial catalysts have been reported, designed to mimic a plethora of chemical transformations, and relevant ex les are highlighted in reviews and scientific reports. Herein, we discuss biomimetics of the metallohydrolase purple acid phosphatase (PAP), ex les of which have been used to showcase synergistic research advances for both the biological and synthetic systems. In particular, we focus on the seminal contribution of our colleague Prof. Ademir Neves, and his group, pioneers in the design and optimization of suitable ligands that mimic the active site of PAP.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Liam Wilson.