scholarly journals Solution structures of the Bacillus cereus metallo-β-lactamase BcII and its complex with the broad spectrum inhibitor R-thiomandelic acid

2013 ◽  
Vol 456 (3) ◽  
pp. 397-407 ◽  
Author(s):  
Andreas Ioannis Karsisiotis ◽  
Christian F. Damblon ◽  
Gordon C. K. Roberts
Keyword(s):  
Antibiotic Resistance ◽  
Bacillus Cereus ◽  
Broad Spectrum ◽  
Active Site ◽  
Solution Structure ◽  
Inhibitor Binding ◽  
Solution Structures ◽  
Micro Organisms ◽  
Flexible Loops

Metallo-β-lactamases are important in antibiotic resistance in micro-organisms. We report the first solution structure of a metallo-β-lactamase and its complex with an inhibitor, allowing the key flexible loops flanking the active site and their role in inhibitor binding to be properly defined.

Solution structure and catalytic mechanism of human protein histidine phosphatase 1

2009 ◽  
Vol 418 (2) ◽  
pp. 337-344 ◽  
Author(s):  
Weibin Gong ◽  
Yifei Li ◽  
Gaofeng Cui ◽  
Jicheng Hu ◽  
Huaming Fang ◽  
...  
Keyword(s):  
Active Site ◽  
Bound States ◽  
Solution Structure ◽  
Catalytic Mechanism ◽  
Imidazole Ring ◽  
Side Chain ◽  
Cellular Functions ◽  
Solution Structures ◽  
Histidine Phosphorylation ◽  
Mutagenesis Study

Protein histidine phosphorylation exists widely in vertebrates, and it plays important roles in signal transduction and other cellular functions. However, knowledge about eukaryotic PHPT (protein histidine phosphatase) is still very limited. To date, only one vertebrate PHPT has been discovered, and two crystal structures of hPHPT1 (human PHPT1) have been solved. However, these two structures gave different ligand-binding sites and co-ordination patterns. In the present paper, we have solved the solution structures of hPHPT1 in both Pi-free and Pi-bound states. Through comparison of the structures, along with a mutagenesis study, we have determined the active site of hPHPT1. In contrast with previous results, our results indicate that the active site is located between helix α1 and loop L5. His53 was identified to be the catalytic residue, and the NH groups of residues His53, Ala54 and Ala96 and the OH group of Ser94 should act as anchors of Pi or substrate by forming H-bonds with Pi. On the basis of our results, a catalytic mechanism is proposed for hPHPT1: the imidazole ring of His53 serves as a general base to activate a water molecule, and the activated water would attack the substrate as a nucleophile in the catalysis; the positively charged side chain of Lys21 can help stabilize the transition state. No similar catalytic mechanism can be found in the EzCatDB database.

scholarly journals The Role of Active Site Flexible Loops in Catalysis and of Zinc in Conformational Stability of Bacillus cereus 569/H/9 β-Lactamase

2016 ◽  
Vol 291 (31) ◽  
pp. 16124-16137 ◽  
Author(s):  
Caroline Montagner ◽  
Michaël Nigen ◽  
Olivier Jacquin ◽  
Nicolas Willet ◽  
Mireille Dumoulin ◽  
...  
Keyword(s):  
Bacillus Cereus ◽  
Active Site ◽  
Conformational Stability ◽  
Flexible Loops

The assemblage of covalent and metal binding dual functional scaffold for cross-class metallo-β-lactamases inhibition

2019 ◽  
Vol 11 (18) ◽  
pp. 2381-2394 ◽  
Author(s):  
Cheng Chen ◽  
Ya Liu ◽  
Yue-Juan Zhang ◽  
Ying Ge ◽  
Jin-E Lei ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Antibiotic Resistance ◽  
Broad Spectrum ◽  
Active Site ◽  
Metal Binding ◽  
Covalent Bond ◽  
Antibacterial Efficacy ◽  
Dual Functional ◽  
Potent Inhibition

Aim: The discovery and development of novel broad-spectrum MβLs inhibitors are urgent to overcome antibiotic resistance mediated by MβLs. Methods & results: Herein, the synthesized 21 compounds exhibited potent inhibition to the clinically important MβLs (NDM-1, IMP-1 and ImiS) and effectively restored the antibacterial efficacy of cefazolin and imipenem against Escherichia coli harboring MβLs. 5b was first identified to be dual functional broad-spectrum MβLs inhibitor through assemblage of covalent and metal binding scaffold, which irreversibly inhibited B1, B2 MβLs via forming a Se–S covalent bond, and competitively inhibited B3 MβLs by coordinating the metals at active site. Conclusion: The designed compounds can serve as potent broad-spectrum MβLs inhibitors and combat MβLs-producing ‘superbug’ in combination with β-lactams.

scholarly journals Mutation-Based Antibiotic Resistance Mechanism in Methicillin-Resistant Staphylococcus aureus Clinical Isolates

2021 ◽  
Vol 14 (5) ◽  
pp. 420
Author(s):  
Tanveer Ali ◽  
Abdul Basit ◽  
Asad Mustafa Karim ◽  
Jung-Hun Lee ◽  
Jeong-Ho Jeon ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antibiotic Resistance ◽  
Active Site ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Meca Gene ◽  
Resistance Mechanism ◽  
Ligand Docking ◽  
Clinical Samples ◽  
Allosteric Site ◽  
Methicillin Resistant

β-Lactam antibiotics target penicillin-binding proteins and inhibit the synthesis of peptidoglycan, a crucial step in cell wall biosynthesis. Staphylococcus aureus acquires resistance against β-lactam antibiotics by producing a penicillin-binding protein 2a (PBP2a), encoded by the mecA gene. PBP2a participates in peptidoglycan biosynthesis and exhibits a poor affinity towards β-lactam antibiotics. The current study was performed to determine the diversity and the role of missense mutations of PBP2a in the antibiotic resistance mechanism. The methicillin-resistant Staphylococcus aureus (MRSA) isolates from clinical samples were identified using phenotypic and genotypic techniques. The highest frequency (60%, 18 out of 30) of MRSA was observed in wound specimens. Sequence variation analysis of the mecA gene showed four amino acid substitutions (i.e., E239K, E239R, G246E, and E447K). The E239R mutation was found to be novel. The protein-ligand docking results showed that the E239R mutation in the allosteric site of PBP2a induces conformational changes in the active site and, thus, hinders its interaction with cefoxitin. Therefore, the present report indicates that mutation in the allosteric site of PBP2a provides a more closed active site conformation than wide-type PBP2a and then causes the high-level resistance to cefoxitin.

1.85 Å Resolution Structure of the ZincII β-Lactamase from Bacillus cereus

1998 ◽  
Vol 54 (3) ◽  
pp. 313-323 ◽  
Author(s):  
Andrea Carfi ◽  
Emile Duée ◽  
Moreno Galleni ◽  
Jean-Marie Frère ◽  
Otto Dideberg
Keyword(s):  
Bacillus Cereus ◽  
Active Site ◽  
Metal Ion ◽  
Wide Spectrum ◽  
Zinc Ion ◽  
Beta Lactamases ◽  
Carbonate Ion ◽  
Class B ◽  
Bivalent Metal Ions ◽  
Using Data

Class B \beta-lactamases are wide spectrum enzymes which require bivalent metal ions for activity. The structure of the class B zinc-ion-dependent β-lactamase from Bacillus cereus (BCII) has been refined at 1.85 Å resolution using data collected on cryocooled crystals (100 K). The enzyme from B. cereus has a molecular mass of 24 946 Da and is folded into a \beta-sandwich structure with helices on the external faces. The active site is located in a groove running between the two \beta-sheets [Carfi et al. (1995). EMBO J. 14, 4914–4921]. The 100 K high-resolution BCII structure shows one fully and one partially occupied zinc site. The zinc ion in the fully occupied site (the catalytic zinc) is coordinated by three histidines and one water molecule. The second zinc ion is at 3.7 Å from the first one and is coordinated by one histidine, one cysteine, one aspartate and one unknown molecule (which is most likely to be a carbonate ion). In the B. cereus zinc \beta-lactamase the affinity for the second metal ion is low at the pH of crystallization (Kd = 25 mM, 293 K; [Baldwin et al. (1978). Biochem. J. 175, 441–447] and the dissociation constant of the second zinc ion thus apparently decreased at the cryogenic temperature. In addition, the structure of the apo enzyme was determined at 2.5 Å resolution. The removal of the zinc ion by chelating agents causes small changes in the active-site environment.

scholarly journals Predicting allosteric mutants that increase activity of a major antibiotic resistance enzyme

2017 ◽  
Vol 8 (9) ◽  
pp. 6484-6492 ◽  
Author(s):  
M. J. Latallo ◽  
G. A. Cortina ◽  
S. Faham ◽  
R. K. Nakamoto ◽  
P. M. Kasson
Keyword(s):  
Machine Learning ◽  
Antibiotic Resistance ◽  
Active Site ◽  
Beta Lactamase ◽  
Active Site Residues ◽  
Conformational Ensembles

Allosteric mutations increasingkcatin a beta lactamase act by changing conformational ensembles of active-site residues identified by machine learning.

scholarly journals Antimicrobial Activity of Biosynthesized Silver Nanoparticles Compared to Standard Antibiotics Used in ORL Infections

2019 ◽  
Vol 70 (7) ◽  
pp. 2571-2573
Author(s):  
Alina Andreea Tischer (Tucuina) ◽  
Delia Berceanu Vaduva ◽  
Nicolae Balica ◽  
Alina Heghes ◽  
Adelina Cheveresan ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Silver Nanoparticles ◽  
Antibiotic Resistance ◽  
Adverse Effects ◽  
Infectious Diseases ◽  
Broad Spectrum ◽  
Bacterial Infections ◽  
New Antibiotics ◽  
Recorded Data

In recent years, bacterial infections in hospitals have grown particularly due to the development of antibiotic resistance. Recent research targets the discovery of new antibiotics that exhibit broad spectrum of action without adverse effects or minimizing adverse effects. In this study, the activity of biosynthesized silver nanoparticles against three bacteria commonly found in infectious diseases in the ORL sphere was evaluated. The recorded data revealed an activity comparable to that of the standard antibiotics used in these types of infections, with the observation that the activity of the nanoparticles could also be observed in the particular cases of antibiotic resistance.

Antimicrobial activity of selected Iranian medicinal plants against a broad spectrum of pathogenic and drug multiresistant micro-organisms

2014 ◽  
Vol 59 (4) ◽  
pp. 412-421 ◽  
Author(s):  
A. Abedini ◽  
V. Roumy ◽  
S. Mahieux ◽  
A. Gohari ◽  
M.M. Farimani ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Medicinal Plants ◽  
Broad Spectrum ◽  
Micro Organisms

Solution Structure of a Natural CPPC Active Site Variant, the Reduced Form of Thioredoxinh1 from Poplar†,‡

Biochemistry ◽  
2005 ◽  
Vol 44 (6) ◽  
pp. 2001-2008 ◽  
Author(s):  
Nicolas Coudevylle ◽  
Aurélien Thureau ◽  
Christine Hemmerlin ◽  
Eric Gelhaye ◽  
Jean-Pierre Jacquot ◽  
...  
Keyword(s):  
Active Site ◽  
Solution Structure ◽  
Reduced Form
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