Broad spectrum antibiotic-degrading metallo-β-lactamases are phylogenetically diverse

Pedroso, Marcelo Monteiro; Waite, David W.; Melse, Okke; Wilson, Liam A.; Mitić, Nataša; McGeary, Ross P.; Antes, Iris; Guddat, L.W.; Hugenholtz, Philip; Schenk, Gerhard

doi:10.1007/s13238-020-00736-4

Cited by 22 publications

(61 citation statements)

References 15 publications

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“…In summary, we previously demonstrated that marine environments harbour a large number of MBLs from the B3 subgroup 42 . Of particular interest among those MBLs are those from the marine organisms N. pentaromativorans (MIM-1) and S. agarivorans (SAM-1, formerly known as MIM-2) as we previously already demonstrated that they are not only potent MBLs, but are also capable to hydrolyze quorum-sensing molecules 20 , 21 .…”

Section: Resultsmentioning

confidence: 65%

“…The zinc binding sites in MIM-1 and SAM-1 (Fig. 2) are defined by a motif (HHH/DHH), that is characteristic for the majority of MBLs of the B3 subgroup 42 . The Zn-Zn distances in MIM-1 (4.02 Å) and SAM-1 (3.40 Å) are comparable with those observed in other B3 MBLs, i.e.…”

Section: Resultsmentioning

confidence: 99%

“…Specifically, the two metal ions in the α and β sites (Zn1 and Zn2) of MIM-1 and SAM-1 are coordinated by His116, His118 and His194 (α site), and Asp120, His121 and His260/259 (β site), respectively. The motif HHH/DHH for the ligands interacting with the metals in the active site is a characteristic feature for MBLs belonging to the B3 subgroup 42 . Additional features in MIM-1 and SAM-1 include the presence of Gln157, located on loop 1 (Figs.…”

Section: Resultsmentioning

confidence: 99%

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Structure and mechanism of potent bifunctional β-lactam- and homoserine lactone-degrading enzymes from marine microorganisms

Selleck

Pedroso

Wilson

et al. 2020

Sci Rep

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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 examples 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 diverse substrates by these enzymes. Antibiotic resistance is a rising socioeconomic problem due to the lack of industrial antibiotic development over the last two decades 1,2. Although new antibiotic substances are developed continuously by academic groups, very few are transferred into industrial production and clinical application. Moreover, there is a lack of new (bio) chemical strategies to overcome antibiotic resistance, and although many of the newly developed antibiotic compounds may display novel structural features they mostly act upon the same cellular mechanisms (i.e. inhibition of cell wall biosynthesis, blocking ribosome function or cell replication). Therefore, there is an imminent global threat that available antibiotic substances may not be effective against ever faster evolving microbial pathogens; the most prominent among these pathogens are listed by the WHO and categorised in class 1-3 threat levels 3,4. To meet the societal challenges exerted by these microbial pathogens, new mechanisms to combat antibiotic

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Section: Resultsmentioning

confidence: 65%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Structure and mechanism of potent bifunctional β-lactam- and homoserine lactone-degrading enzymes from marine microorganisms

Selleck

Pedroso

Wilson

et al. 2020

Sci Rep

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Section: Carbapenemases: the Nightmare Of Anti‐infective Therapies Based On β‐Lactam Antibioticsmentioning

confidence: 99%

“…Thus, there are marked differences between these two types of enzymes, both in the mechanism of action and the structural topology, which hinders the development of effective inhibitors based on previous scaffolds. [60,[64][65][66] Nowadays, there is a great deal of concern about the impact of the infections caused by carbapenem-resistant A. baumannii, P. aeruginosa, and Enterobacteriaceae that are frequently found in hospitalized patients fitted with invasive devices or exposed to extended antibiotic regimens. [67][68][69][70] Of particular concern is the global incidence of class A carbapenemases, such as KPC, SME, IMI, NMC-A, and GES-2, carbapenem-hydrolyzing class D -lactamases, such as OXA-23, OXA-24/40, and OXA-48, as well as metallo--lactamases such as IMP, VIM, and NDM (Figure 4).…”

Section: Carbapenemases: the Nightmare Of Anti-infective Therapies Based On -Lactam Antibioticsmentioning

confidence: 99%

Bicyclic Boronate β‐Lactamase Inhibitors: The Present Hope against Deadly Bacterial Pathogens

Lence

González‐Bello

2021

Advanced Therapeutics

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The use of β‐lactamase inhibitors in combination with β‐lactam antibiotics is an emerging area in drug discovery. This strategy allows the restoration of the therapeutic efficacy of these antibiotics in clinical use against multiresistant bacteria. These pathogens are drug resistant because they express β‐lactamase enzymes, which prevent the antibiotic therapeutic action by catalyzing the hydrolysis of the β‐lactam ring. These enzymes are quite diverse in both their structural architecture and hydrolytic capability, as well as in the mechanism of action. The ever‐increasing emergence of pathogens that are capable of coproducing different types of β‐lactamases has triggered the search for ultrabroad‐spectrum inhibitors capable of deactivating both serine‐ and metallo‐β‐lactamases. A recent breakthrough in this long‐pursued and unmet need is the discovery of bicyclic boronate inhibitors, specifically taniborbactam, VNRX‐7145, and QPX7728, which are currently under clinical development in combination with cefepime, ceftibuten, and QPX2014, respectively. The present article highlights the therapeutic potential of these inhibitors and their spectrum of efficacy is compared with those of other β‐lactam/β‐lactamase inhibitor combinations recently approved by the food and drug administration. The molecular basis of the ultrabroad‐spectrum of activity of boron‐based inhibitors is also discussed, on the basis of the available crystal structures and the results of computational studies.

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Structural and Functional Insight into the Mechanism of the Fe−S Cluster‐Dependent Dehydratase from Paralcaligenes ureilyticus

Bayaraa

Lonhienne

Sutiono

et al. 2022

Chemistry A European J

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Enzyme-catalyzed reaction cascades play an increasingly important role for the sustainable manufacture of diverse chemicals from renewable feedstocks. For instance, dehydratases from the ilvD/EDD superfamily have been embedded into a cascade to convert glucose via pyruvate to isobutanol, a platform chemical for the production of aviation fuels and other valuable materials. These dehydratases depend on the presence of both a FeÀ S cluster and a divalent metal ion for their function. However, they also represent the rate-limiting step in the cascade. Here, catalytic parameters and the crystal structure of the dehydratase from Paralcaligenes ureilyticus (PuDHT, both in presence of Mg 2 + and Mn 2 + ) were investigated. Rate measurements demonstrate that the presence of stoichiometric concentrations Mn 2 + promotes higher activity than Mg 2 + , but at high concentrations the former inhibits the activity of PuDHT. Molecular dynamics simulations identify the position of a second binding site for the divalent metal ion. Only binding of Mn 2 + (not Mg 2 + ) to this site affects the ligand environment of the catalytically essential divalent metal binding site, thus providing insight into an inhibitory mechanism of Mn 2 + at higher concentrations. Furthermore, in silico docking identified residues that play a role in determining substrate binding and selectivity. The combined data inform engineering approaches to design an optimal dehydratase for the cascade.

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Broad spectrum antibiotic-degrading metallo-β-lactamases are phylogenetically diverse

Abstract: Broad spectrum antibiotic-degrading metalloβ-lactamases are phylogenetically diverse Dear Editor,

Cited by 22 publications

References 15 publications

Structure and mechanism of potent bifunctional β-lactam- and homoserine lactone-degrading enzymes from marine microorganisms

Structure and mechanism of potent bifunctional β-lactam- and homoserine lactone-degrading enzymes from marine microorganisms

Bicyclic Boronate β‐Lactamase Inhibitors: The Present Hope against Deadly Bacterial Pathogens

Structural and Functional Insight into the Mechanism of the Fe−S Cluster‐Dependent Dehydratase from Paralcaligenes ureilyticus

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