Academic literature on the topic 'Beta - Lactam Based Molecules'
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Journal articles on the topic "Beta - Lactam Based Molecules"
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Shlaes, D. M., and C. Currie-McCumber. "Mutations altering substrate specificity in OHIO-1, and SHV-1 family β-lactamase." Biochemical Journal 284, no. 2 (June 1, 1992): 411–15. http://dx.doi.org/10.1042/bj2840411.
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The OHIO-1 beta-lactamase does not normally hydrolyse oxyimino-beta-lactam substrates like cefotaxime, ceftriaxone, ceftazidime or aztreonam. We were able to select spontaneous mutants of an OHIO-1-bearing strain of Escherichia coli using the antibiotic substrates listed above by enrichment methods of frequencies of 10(-8)-10(-10) for all antibiotics except ceftazidime (frequency less than 10(-10)). Most mutants with increased resistance to the other beta-lactams were also more resistant to ceftazidime. Mutations identified by DNA sequencing included a Gly238----Ser238 substitution identical with the SHV-2 mutation previously described, cysteine and valine substitutions at the identical site, and a Gly242----Cys242 substitution. The Cys238 and Cys242 mutant enzymes had less affinity for aztreonam than had the other mutant enzymes. Hydrolysis of cefotaxime, but not cephaloridine, by the cysteine-substituted enzymes was inhibited by p-chloromercuribenzoate. The mutant enzymes had, in general, greater affinity for the mechanism-based inhibitors sulbactam, clavulanic acid and tazobactam. These results suggest two non-mutually exclusive hypotheses for the structural role of substitutions in this area of the enzyme. Either potential hydrogen-bond donors, such as serine and cysteine, interact directly with the beta-lactam molecules, or the steric bulk of these substitutions distorts the beta-pleated sheet such that the beta-lactam is held in a position favourable for stable binding and catalysis. Finally, our data raise questions about a strategy relying on oligonucleotide-probe technology to detect such mutations, because of the variety of substitutions that give rise to similar phenotypes.
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Pestana-Nobles, Roberto, Yani Aranguren-Díaz, Elwi Machado-Sierra, Juvenal Yosa, Nataly J. Galan-Freyle, Laura X. Sepulveda-Montaño, Daniel G. Kuroda, and Leonardo C. Pacheco-Londoño. "Docking and Molecular Dynamic of Microalgae Compounds as Potential Inhibitors of Beta-Lactamase." International Journal of Molecular Sciences 23, no. 3 (January 31, 2022): 1630. http://dx.doi.org/10.3390/ijms23031630.
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Bacterial resistance is responsible for a wide variety of health problems, both in children and adults. The persistence of symptoms and infections are mainly treated with β-lactam antibiotics. The increasing resistance to those antibiotics by bacterial pathogens generated the emergence of extended-spectrum β-lactamases (ESBLs), an actual public health problem. This is due to rapid mutations of bacteria when exposed to antibiotics. In this case, β-lactamases are enzymes used by bacteria to hydrolyze the beta-lactam rings present in the antibiotics. Therefore, it was necessary to explore novel molecules as potential β-lactamases inhibitors to find antibacterial compounds against infection caused by ESBLs. A computational methodology based on molecular docking and molecular dynamic simulations was used to find new microalgae metabolites inhibitors of β-lactamase. Six 3D β-lactamase proteins were selected, and the molecular docking revealed that the metabolites belonging to the same structural families, such as phenylacridine (4-Ph), quercetin (Qn), and cryptophycin (Cryp), exhibit a better binding score and binding energy than commercial clinical medicine β-lactamase inhibitors, such as clavulanic acid, sulbactam, and tazobactam. These results indicate that 4-Ph, Qn, and Cryp molecules, homologous from microalgae metabolites, could be used, likely as novel β-lactamase inhibitors or as structural templates for new in-silico pharmaceutical designs, with the possibility of combatting β-lactam resistance
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Vitus Silago. "Beta-lactam antibiotics and extended spectrum beta-lactamases." GSC Advanced Research and Reviews 9, no. 2 (November 30, 2021): 015–24. http://dx.doi.org/10.30574/gscarr.2021.9.2.0200.
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Extended spectrum beta-lactamases (ESBLs) are enzymes produced by bacteria, mostly members of the family Enterobacteriaceae commonly Escherichia coli and Klebsiella pneumoniae. ESBLs hydrolyze the beta-lactam ring of beta-lactam antibiotics making these antibiotics ineffective therefore rendering the bacteria resistance against beta-lactam antibiotics. The global upsurge of ESBLs producing bacteria causing both hospital and community acquired infections mostly urinary tract infections, pneumonia and bloodstream infections, threatens the effectiveness of infectious diseases treatment. ESBL families; TEM, SHV and CTX-M are globally disseminated and frequently detected in clinical isolates as well as colonization and contamination isolates. Various laboratory detection methods of ESBLs producing Gram negative bacteria are available. These methods; phenotypic methods, automated methods and molecular-based methods are varying in sensitivity and specificity, need of technical expertise, and rapidness. Therefore, they should be clearly understood before being employed for routine or research use for detection of ESBLs production among Enterobacteriaceae. In addition, understanding the mode of action and mechanisms of resistance to beta-lactam antibiotics, and the epidemiology of ESBLs producing bacteria is of paramount.
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Ahmadvand, Parvaneh, Johannetsy J. Avillan, Jacob A. Lewis, Douglas R. Call, and ChulHee Kang. "Characterization of Interactions between CTX-M-15 and Clavulanic Acid, Desfuroylceftiofur, Ceftiofur, Ampicillin, and Nitrocefin." International Journal of Molecular Sciences 23, no. 9 (May 7, 2022): 5229. http://dx.doi.org/10.3390/ijms23095229.
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Cefotaximase-Munich (CTX-M) extended-spectrum beta-lactamases (ESBLs) are commonly associated with Gram-negative, hospital-acquired infections worldwide. Several beta-lactamase inhibitors, such as clavulanate, are used to inhibit the activity of these enzymes. To understand the mechanism of CTX-M-15 activity, we have determined the crystal structures of CTX-M-15 in complex with two specific classes of beta-lactam compounds, desfuroylceftiofur (DFC) and ampicillin, and an inhibitor, clavulanic acid. The crystal structures revealed that Ser70 and five other residues (Lys73, Tyr105, Glu166, Ser130, and Ser237) participate in catalysis and binding of those compounds. Based on analysis of steady-state kinetics, thermodynamic data, and molecular docking to both wild-type and S70A mutant structures, we determined that CTX-M-15 has a similar affinity for all beta-lactam compounds (ceftiofur, nitrocefin, DFC, and ampicillin), but with lower affinity for clavulanic acid. A catalytic mechanism for tested β-lactams and two-step inhibition mechanism of clavulanic acid were proposed. CTX-M-15 showed a higher activity toward DFC and nitrocefin, but significantly lower activity toward ampicillin and ceftiofur. The interaction between CTX-M-15 and both ampicillin and ceftiofur displayed a higher entropic but lower enthalpic effect, compared with DFC and nitrocefin. DFC, a metabolite of ceftiofur, displayed lower entropy and higher enthalpy than ceftiofur. This finding suggests that compounds containing amine moiety (e.g., ampicillin) and the furfural moiety (e.g., ceftiofur) could hinder the hydrolytic activity of CTX-M-15.
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Anggini, Pragati Wira, Syahidah Asma Amanina, Salwa Rainha Asyura, and Romario Dion. "In silico Study of Essential Oil of Bambusa vulgaris Leaves as an Anti Beta-lactamase Compound." Molecular and Cellular Biomedical Sciences 6, no. 3 (November 2, 2022): 147. http://dx.doi.org/10.21705/mcbs.v6i3.278.
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Background: Klebsiella pneumoniae is known as an extended spectrum beta (β)-lactamases (ESBLs)-producing bacteria, which produces enzymes that cause resistance to β-lactam antibiotics by degrading β-lactam ring. A solution is needed to prevent the degradation of the β-lactam ring. In this in silico study, combining β-lactam antibiotics with secondary metabolites has the possibility to inhibit the active site of the β-lactamase enzyme. This study aimed to explore the potential of the essential oil of yellow bamboo (Bambusa vulgaris) leaves as inhibitors of β-lactamase. Materials and methods: This research was conducted by simulating molecular docking to determine the interaction of ligands with proteins, pharmacological tests of compounds based on the Lipinski’s rule of five, and ligand toxicity tests with pkCSM. Results: The free bond energy values (∆G) were in the range of -4.3 to -8.0 kcal/mol. The ligands with the best ∆G value were sulfur pentafluoride (-8.0 kcal/mol), squalene (-7.3 kcal/mol), 3-aminodibenzofuran (-7.1 kcal/mol), and 2- monolaurin (-5.5 kcal/mol). Secondary metabolites from the essential oil of B. vulgaris leaves fulfilled Lipinski’s rule of five, so that oral use can be carried out except for squalene and tridecane. Conclusion: Secondary metabolite compounds in the essential oil that have potential as oral drugs based on the Lipinski pharmacological test and the pkCSM toxicity test are dipivaloylmethane, β-ocimene, 2-monolaurin, and undecane. Keywords: β-lactamase, Bambusa vulgaris, essential oil, Klebsiella pneumoniae
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Anant, Prem Singh, and Pratima Gupta. "Application of machine learning in understanding bioactivity of beta-lactamase AmpC." Journal of Physics: Conference Series 2273, no. 1 (May 1, 2022): 012005. http://dx.doi.org/10.1088/1742-6596/2273/1/012005.
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Abstract The ability of microorganisms like bacteria to develop mechanisms against the treatment is becoming a concern globally. This topic of concern is called Antimicrobial Resistance aka AMR. In this study, with the help of machine learning algorithms we are trying to evaluate the activity of molecules that have been tested experimentally either to bind or not bind the beta lactamases. Machine learning is a technique for analysis of data which teaches the computers what naturally comes to living organisms. Beta lactamases are diverse family of microbial enzymes that hydrolyse the cyclic amide bond of susceptible to beta-lactam antibiotics. Studying the effects and functioning of beta lactamases enzymes can provide better insights into the AMR mechanism adopted by the microorganisms. AMR is one of the top 10 global public health threats facing humanity in this era. Therefore, finding potential compounds that can combat these microorganisms is very important. Here, we have considered few plant-based flavonoids and terpenoids and checked the bioactivity against these beta lactamases containing microorganisms by using machine learning algorithms. A large dataset having more than 62,000 compounds and their pPotency values against beta lactamase AmpC was obtained from ChEMBL and employed in QSAR (quantitative structure activity relationship) model in order to understand the origin of their bioactivity. Several set of fingerprint descriptors and predictive models were constructed and results are obtained.
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Krishnamoorthy, Rajapandiyan, Jegan Athinarayanan, Vaiyapuri Subbarayan Periyasamy, Mohammad A. Alshuniaber, Ghedeir Alshammari, Mohammed Jamal Hakeem, Mohammed Asif Ahmed, and Ali A. Alshatwi. "Antibacterial Mechanisms of Zinc Oxide Nanoparticle against Bacterial Food Pathogens Resistant to Beta-Lactam Antibiotics." Molecules 27, no. 8 (April 12, 2022): 2489. http://dx.doi.org/10.3390/molecules27082489.
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The increase in β-lactam-resistant Gram-negative bacteria is a severe recurrent problem in the food industry for both producers and consumers. The development of nanotechnology and nanomaterial applications has transformed many features in food science. The antibacterial activity of zinc oxide nanoparticles (ZnO NPs) and their mechanism of action on β-lactam-resistant Gram-negative food pathogens, such as Escherichia coli, Pseudomonas aeruginosa, Salmonella typhi, Serratia marcescens, Klebsiella pneumoniae, and Proteus mirabilis, are investigated in the present paper. The study results demonstrate that ZnO NPs possesses broad-spectrum action against these β-lactamase-producing strains. The minimal inhibitory and minimal bactericidal concentrations vary from 0.04 to 0.08 and 0.12 to 0.24 mg/mL, respectively. The ZnO NPs elevate the level of reactive oxygen species (ROS) and malondialdehyde in the bacterial cells as membrane lipid peroxidation. It has been confirmed from the transmission electron microscopy image of the treated bacterial cells that ZnO NPs diminish the permeable membrane, denature the intracellular proteins, cause DNA damage, and cause membrane leakage. Based on these findings, the action of ZnO NPs has been attributed to the fact that broad-spectrum antibacterial action against β-lactam-resistant Gram-negative food pathogens is mediated by Zn2+ ion-induced oxidative stress, actions via lipid peroxidation and membrane damage, subsequently resulting in depletion, leading to β-lactamase enzyme inhibition, intracellular protein inactivation, DNA damage, and eventually cell death. Based on the findings of the present study, ZnO NPs can be recommended as potent broad-spectrum antibacterial agents against β-lactam-resistant Gram-negative pathogenic strains.
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Minhas, Gurdeep S., and Simon Newstead. "Structural basis for prodrug recognition by the SLC15 family of proton-coupled peptide transporters." Proceedings of the National Academy of Sciences 116, no. 3 (January 2, 2019): 804–9. http://dx.doi.org/10.1073/pnas.1813715116.
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A major challenge in drug development is the optimization of intestinal absorption and cellular uptake. A successful strategy has been to develop prodrug molecules, which hijack solute carrier (SLC) transporters for active transport into the body. The proton-coupled oligopeptide transporters, PepT1 and PepT2, have been successfully targeted using this approach. Peptide transporters display a remarkable capacity to recognize a diverse library of di- and tripeptides, making them extremely promiscuous and major contributors to the pharmacokinetic profile of several important drug classes, including beta-lactam antibiotics and antiviral and antineoplastic agents. Of particular interest has been their ability to recognize amino acid and peptide-based prodrug molecules, thereby providing a rational approach to improving drug transport into the body. However, the structural basis for prodrug recognition has remained elusive. Here we present crystal structures of a prokaryotic homolog of the mammalian transporters in complex with the antiviral prodrug valacyclovir and the peptide-based photodynamic therapy agent, 5-aminolevulinic acid. The valacyclovir structure reveals that prodrug recognition is mediated through both the amino acid scaffold and the ester bond, which is commonly used to link drug molecules to the carrier’s physiological ligand, whereas 5-aminolevulinic acid makes far fewer interactions compared with physiological peptides. These structures provide a unique insight into how peptide transporters interact with xenobiotic molecules and provide a template for further prodrug development.
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Godijk, Noortje G., Martin C. J. Bootsma, Henri C. van Werkhoven, Valentijn A. Schweitzer, Sabine C. de Greeff, Annelot F. Schoffelen, and Marc J. M. Bonten. "Does plasmid-based beta-lactam resistance increase E. coli infections: Modelling addition and replacement mechanisms." PLOS Computational Biology 18, no. 3 (March 14, 2022): e1009875. http://dx.doi.org/10.1371/journal.pcbi.1009875.
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Infections caused by antibiotic-resistant bacteria have become more prevalent during past decades. Yet, it is unknown whether such infections occur in addition to infections with antibiotic-susceptible bacteria, thereby increasing the incidence of infections, or whether they replace such infections, leaving the total incidence unaffected. Observational longitudinal studies cannot separate both mechanisms. Using plasmid-based beta-lactam resistant E. coli as example we applied mathematical modelling to investigate whether seven biological mechanisms would lead to replacement or addition of infections. We use a mathematical neutral null model of individuals colonized with susceptible and/or resistant E. coli, with two mechanisms implying a fitness cost, i.e., increased clearance and decreased growth of resistant strains, and five mechanisms benefitting resistance, i.e., 1) increased virulence, 2) increased transmission, 3) decreased clearance of resistant strains, 4) increased rate of horizontal plasmid transfer, and 5) increased clearance of susceptible E. coli due to antibiotics. Each mechanism is modelled separately to estimate addition to or replacement of antibiotic-susceptible infections. Fitness costs cause resistant strains to die out if other strain characteristics are maintained equal. Under the assumptions tested, increased virulence is the only mechanism that increases the total number of infections. Other benefits of resistance lead to replacement of susceptible infections without changing the total number of infections. As there is no biological evidence that plasmid-based beta-lactam resistance increases virulence, these findings suggest that the burden of disease is determined by attributable effects of resistance rather than by an increase in the number of infections.
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Srivastava, Abhishikha, Neelja Singhal, Manisha Goel, Jugsharan Singh Virdi, and Manish Kumar. "Identification of Family Specific Fingerprints inβ-Lactamase Families." Scientific World Journal 2014 (2014): 1–7. http://dx.doi.org/10.1155/2014/980572.
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Beta-lactamases are a superfamily of enzymes which degrade theβ-lactam class of antibiotics. They are produced endogenously by the bacterial cells, which when exposed to theβ-lactam class of antibiotics inactivate them by cleaving theβ-lactam ring. Based on the presence or absence of metallic ligand,β-lactamases have been divided into two broad functional classes.β-Lactamases are a constitutively evolving and expanding superfamily of enzymes, which could be further subdivided on the basis of presence/absence of conserved motifs. In the present study we have used the MEME/MAST suit to identify the patterns/motifs which are specific to a particular family or subfamily ofβ-lactamases. The family specific patterns/motifs can be also useful in recognizing and assigning newly discoveredβ-lactamases to one or the other family or subfamily. Cross-validation showed that the proposed method is highly sensitive and specific. We have also designed a webserver, LactFP, for this purpose.
Dissertations / Theses on the topic "Beta - Lactam Based Molecules"
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Nichols, Derek Allen. "Structure-Based Design of Novel Inhibitors and Ultra High Resolution Analysis of CTX-M Beta-Lactamase." Scholar Commons, 2014. https://scholarcommons.usf.edu/etd/5284.
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The emergence of CTX-M class-A extended-spectrum β-lactamases, which confer resistance to second and third-generation cephalosporins, poses a serious health threat to the public. CTX-M β-lactamases use a catalytic serine to hydrolyze the β-lactam ring. Specifically, the hydrolysis reaction catalyzed by CTX-M β-lactamase proceeds through a pre-covalent complex, a high-energy tetrahedral acylation intermediate, a low-energy acyl-enzyme complex, a high-energy tetrahedral deacylation intermediate after attack via a catalytic water, and lastly, the hydrolyzed β-lactam ring product which is released from the enzyme complex. The crystallographic structure of CTX-M at sub-angstrom resolution has enabled us to study enzyme catalysis as well as perform computational molecular docking in our efforts to develop new inhibitors against CTX-M. The goal of this project was to determine the hydrogen bonding network and proton transfer process at different stages of the reaction pathway as well as develop novel inhibitors against CTX-M β-lactamases. The results I have obtained from the project have elucidated the catalytic mechanism of CTX-M β-lactamase in unprecedented detail and facilitated the development of novel inhibitors for antibiotic drug discovery.
The first aim of the project focused on developing high affinity inhibitors against class A β-lactamase using a structure-based drug discovery approach, which ultimately led to the identification of CTX-M9 inhibitors with nanomolar affinity. Compound design was based on the initial use of computational molecular docking results along with x-ray crystal structures with known inhibitors bound in the active site. In addition, chemical synthesis was used to build and extend the existing inhibitor scaffold to improve affinity to CTX-M9 and related serine β-lactamases. Through a fragment-based screening approach, we recently identified a novel non-covalent tetrazole-containing inhibitor of CTX-M. Structure-based design was used to improve the potency of the original tetrazole lead compound more than 200-fold with the use of small, targeted structural modifications. A series of compounds were used to probe specific binding hotspots present in CTX-M. The designed compounds represent the first nM-affinity non-covalent inhibitors of a class A β-lactamase. The complex structures of these potent compounds have been solved using high resolution x-ray crystallography at ~ 1.2-1.4 Å, which provides valuable insight about ligand binding and future inhibitor design against class A β-lactamases.
Specifically, the first aim of the project was to use ultra-high resolution x-ray crystallography to study β-lactamase catalysis. Through the use of ultra-high resolution x-ray crystallography with non-covalent and covalent inhibitors, I was able to structurally characterize the critical stages of the enzyme mechanism. Here we report a series of ultra-high resolution x-ray crystallographic structures that reveal the proton transfer process for the early stages of the class A β-lactamase catalytic mechanism. The structures obtained include an a 0.89 Å crystal structure of CTX-M β-lactamase in complex with a recently-developed 89 nM non-covalent inhibitor, and a 0.80 Å structure in complex with an acylation transition state boronic acid inhibitor. Nearly all the hydrogen atoms in the active site, including those on the ligand, polar protein side chains and catalytic water, can be identified in the unbiased difference electron density map. Most surprisingly, compared with a previously determined 0.88 Å apo structure determined under the same conditions, the hydrogen-bonding network has undergone a series of reshuffling upon the binding of the non-covalent ligand. Two key catalytic residues, Lys73 and Glu166, appear to have both changed from a charged state to being neutral. Interestingly, structural evidence suggests the presence of a low barrier hydrogen bond (LBHB) shared between Lys73 and Ser70. These unprecedented detailed snapshots offer direct evidence that ligand binding can alter the pKa's of polar protein side chains and their affinities for protons. Such effects can be a common mechanism utilized by enzymes to facilitate the proton transfer process of a reaction pathway. They also have important implications for computational modeling of protein-ligand interactions. Ultra-high resolution x-ray crystallography allowed us to determine the hydrogen atom positions for key active site residues involved in catalysis. As a result, the ability to characterize the hydrogen bonding network led to the determination of the specific proton transfer process that occurs during the reaction stages of the CTX-M β-lactamase mechanism. Overall, the results from this project demonstrate the effectiveness of using ultra high resolution x-ray crystallography as a useful tool to study enzyme catalysis as well as develop and discover novel inhibitors.
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Gustavsson, Eva. "SPR biosensor analysis of [beta]-lactam antibiotics in milk : devoplement and use of assays based on a [beta]-lactam receptor protein /." Uppsala : Swedish Univ. of Agricultural Sciences, 2003. http://www.gbv.de/dms/bs/toc/363528245.pdf.
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Krallis, Myrsini. "Isolation and identification of Beta-Lactam Producing Microorganisms using PCR based methodologies." Thesis, Rhodes University, 1997. http://hdl.handle.net/10962/d1018237.
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The polymerase chain reaction (PCR) was investigated as a potential tool in microbial screening for 13-lactam. producing organisms. Optimization of PCR conditions and the addition of acetamide to the PCR reaction allowed for the successful amplification of the isopenicillin N synthetase (lPNS) gene in S. clavuligerus, S. tanashiensis, S. griseus, S. olivaceus, S. lipmanii, and S. chartreusis. PCR was used to produce a radiolabelled probe from S. clavuligerus that was used to detect analogous genes in bacteria and fungi. Southern blot and dot blot analysis using the lPNS probe revealed the presence of IPNS-like sequences in seventeen organisms. Fourteen of these sequences belonged to known 13-lactam. producing organisms; one unidentified soil isolate; and two non-/3-lactam. producing organisms viz. S. venezuelae ATCC 10712 and S. hygroscopicus ATCC 21703. The lPNS gene was also detected in a 13-lactam producer (S. chartreusis) that had lost its ability to produce antibiotic. It would therefore have been overlooked in a conventional antibiotic screening program. The use of PCR, coupled with Southern hybridization and dot blot analysis, increased the sensitivity and specificity of the antibiotic screening procedures and allowed for the investigation of evolutionary relationships between the eukaryotes and the prokaryotes. A preliminary investigation into the potential use of RAPD PCR and protein fmgerprinting as tools for solving discrepancies in streptomycete identification was conducted. A variety of streptomycete species that were chosen as being representative of a number of numerical taxonomic classes were amplified using various RAPD primers. Streptomycetes appear to be genetically diverse organisms as was reflected by their RAPD and protein profiles. The application of PCR in an antibiotic screening program showed great potential as a specific and sensitive tool in the detection of /3-lactam producers and in the elimination of duplicate strains.
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Badri, Prajakta. "PREDICTION OF HUMAN SYSTEMIC, BIOLOGICALLY RELEVANT PHARMACOKINETIC (PK) PROPERTIES BASED ON QUANTITATIVE STRUCTURE PHARMACOKINETIC RELATIONSHIPS (QSPKR) AND INTERSPECIES PHARMACOKINETIC ALLOMETRIC SCALING (PK-AS)." VCU Scholars Compass, 2010. http://scholarscompass.vcu.edu/etd/124.
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This research developed validated QSPKR and PK-AS models for predicting human systemic PK properties of three, preselected, pharmacological classes of drugs, namely opioids, β-adrenergic receptor ligands (β-ARL) and β-lactam antibiotics (β-LAs) using pertinent human and animal systemic PK properties (fu,, CLtot, Vdss, fe) and their biologically relevant unbound counterparts from the published literature, followed by an assessment of the effect of different molecular descriptors on these PK properties and on the PK-AS slopes for CLtot and Vdss from two species (rat and dog). Lipophilicity (log (D)7.4) and molecular weight (MW) were found to be the most statistically significant and biologically plausible, molecular properties affecting the biologically relevant, systemic PK properties: For compounds with log (D)7.4 > -2.0 and MW < 350 D (e.g., most opioids and β-ARL), increased log (D)7.4 resulted in decreased fu and increased Vdssu, CLtotu and CLnonrenu, indicating the prevalence of hydrophobic interactions with biological membrane/proteins. As result, the final QSPKR models using log (D)7.4 provided acceptable predictions for fu, Vdssu, CLtotu and CLnonrenu. CLnonrenu and CLtotu. For both the datasets, inclusion of drugs undergoing extrahepatic clearance worsened the QSPKR predictions. For compounds with log (D)7.4 < -2.0 and MW > 350 D (e.g., β-LA), increased MW (leading to more hydrogen bond donors/acceptors) resulted in a decrease in fu, likely indicating hydrogen bonding interactions with plasma proteins. In general, it was more difficult to predict PK parameters for β-LAs, as their Vdssu approached plasma volume and CLrenu and CLnonrenu were low - as a result of their high hydrophilicity and large MW, requiring specific drug transporters for distribution and excretion. The PK-AS analysis showed that animal body size accounted for most of the observed variability (r2> 0.80) in systemic PK variables, with single species methods, particularly those using dog, gave the best predictions. The fu correction of PK variables improved goodness of fit and predictability of human PK. There were no apparent effects of molecular properties on the predictions. CLren, CLrenu, CLnonren, and CLnonrenu were the most difficult variables to predict, possibly due to the associated interspecies differences in the metabolism, renal and hepatobiliary drug transporters.
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Ko, Eunhwa. "Exploring Key Orientations of Small Molecules to Disrupt Protein-protein Interactions." Thesis, 2012. http://hdl.handle.net/1969.1/ETD-TAMU-2012-05-10961.
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Protein-protein interactions (PPIs) are attractive targets because of their therapeutic potential. One approach to design small molecules that can disrupt the PPIs is to use structural information of proteins. With this approach, triazole-based peptidomimetics that mimic beta-turn hot-spot regions in neurotrophins were synthesized. The monovalent mimics were assembled into bivalent mimics via a combinatorial method. Three different bivalent mimics were prepared for different studies. Bivalent mimics with long-linkers bound to TrkA or TrkC receptor and showed partial antagonism for the receptors. Other mimics were conjugated with cytotoxic compounds and they were used for TrkC targeted drug delivery. The last group of bivalent mimics previously showed targeted delivery effects for pancreatic cancer cells. In this study, we synthesized Eu-chelated bivalent mimics to perform a competitive binding assay for pancreatic cancer cells.
Previous research in our group focused on design of secondary structures' mimics on rigid scaffolds as "minimalist mimics." We sought to establish structural design criteria for the minimalist mimics, and we wanted to propose that sets of such compounds could mimic local pairs of amino acids in any secondary structures as "universal peptidomimetics." Thus, we designed five compounds, such as oxazoline-, pyrrole-, dyine- "kinked" and "linear" bistrizole-based peptidomimetics, and performed molecular modelings, DFT calculations, and QMD for them to validate our hypothesis.
On the concepts of "minimalist mimics" and "universal peptidomimetics," we developed the C alpha ? C beta vector matching program to evaluate preferred orientations of C alpha - C beta coordinates for secondary structures. We applied the program to omegatides and pyrrolinone-pyrrolidine oligomers. The compounds matched better with strands than for helices.
We expanded the C alpha ? C beta vector matching idea to a method that ranks preferred conformations of small molecules on any combination of three interface side-chains in all structurally characterized PPIs. We developed a PDB mining program (explores key orientation, EKO) to do this, and EKO applied to pyrrolinone-pyrrolidine oligomers to find targets. EKO found several interesting targets, such as AICAR Tfase, GAPDH, and HIV-1 protease. HIV-1 dimerization inhibition and Zhang-Poorman kinetic assays were performed to validate our hypothesis, and the results showed that pyrrolinone-pyrrolidine derivatives inhibited HIV-1 dimerization.
Book chapters on the topic "Beta - Lactam Based Molecules"
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Delpiccolo, Carina M. L., Maitena Martinez-Amezaga, and Ernesto G. Mata. "Recent Approaches Toward the Generation of Molecular Diversity Based on β-Lactam Structures." In Beta-Lactams, 129–62. Cham: Springer International Publishing, 2017. http://dx.doi.org/10.1007/978-3-319-55621-5_5.
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Barber, Michael S., Ulrich Giesecke, Arno Reichert, and Wolfgang Minas. "Industrial Enzymatic Production of Cephalosporin-Based β-Lactams." In Molecular Biotechnolgy of Fungal beta-Lactam Antibiotics and Related Peptide Synthetases, 179–215. Berlin, Heidelberg: Springer Berlin Heidelberg, 2004. http://dx.doi.org/10.1007/b99261.
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Shadab, Mohd, and Mohammad Shahid. "Adjuvant Molecules/Compounds in Combating Bacterial Resistance." In Beta-Lactam Resistance in Gram-Negative Bacteria, 315–24. Singapore: Springer Nature Singapore, 2022. http://dx.doi.org/10.1007/978-981-16-9097-6_19.
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Basu, Anamika, Piyali Basak, and Anasua Sarkar. "Molecular-Docking-Based Anti-Allergic Drug Design." In Pharmaceutical Sciences, 711–26. IGI Global, 2017. http://dx.doi.org/10.4018/978-1-5225-1762-7.ch027.
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Allergens are foreign proteins that when come in contact of part(s) of human body stimulate the production of immunoglobulin types of proteins (antibodies). These allergens react with antibodies (immunoglobulin type E or IgE) produces allergic reactions, also known as immediate-type hypersensitivity reactions. As much as 20% of the general population may be affected by grass pollen as a major cause of allergic disease. EXPB class of proteins are known in the immunological literature as group-1 grass pollen allergens Molecular docking method can be used to identify the predicated the interaction of pollen allergen EXPB1 (Zea m 1), a beta-expansin and group-1 pollen allergen from maize with IgE molecules of human. The World Health Organization recognised allergen immunotherapy, as therapeutics for allergic diseases. RNA Interference (RNAi) is a biological process in which RNA molecules e.g. Small Interfering RNAs (siRNAs) inhibit gene expression, by cleavage and destruction of specific mRNA molecules. Use of Small Interfering RNA (siRNA) is a novel method in the induction of RNA Interference (RNAi), which is a potent method for therapeutics of allergic reactions. Due to various effects of STAT 6 proteins during hypersensitivity reactions caused by pollen allergens, mRNA of STAT6 gene is selected as target gene for allergy therapeutics via Post-Transcriptional Gene Silencing (PTGS). Using molecular docking study a specific sense siRNA is identified as anti allergic drug to treat allergic asthma during immediate type of hypersensitivity reaction, caused by Zea m 1 pollen allergen.
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Basu, Anamika, Piyali Basak, and Anasua Sarkar. "Molecular-Docking-Based Anti-Allergic Drug Design." In Advances in Medical Technologies and Clinical Practice, 232–48. IGI Global, 2016. http://dx.doi.org/10.4018/978-1-5225-0362-0.ch009.
Full textAbstract:
Allergens are foreign proteins that when come in contact of part(s) of human body stimulate the production of immunoglobulin types of proteins (antibodies). These allergens react with antibodies (immunoglobulin type E or IgE) produces allergic reactions, also known as immediate-type hypersensitivity reactions. As much as 20% of the general population may be affected by grass pollen as a major cause of allergic disease. EXPB class of proteins are known in the immunological literature as group-1 grass pollen allergens Molecular docking method can be used to identify the predicated the interaction of pollen allergen EXPB1 (Zea m 1), a beta-expansin and group-1 pollen allergen from maize with IgE molecules of human. The World Health Organization recognised allergen immunotherapy, as therapeutics for allergic diseases. RNA Interference (RNAi) is a biological process in which RNA molecules e.g. Small Interfering RNAs (siRNAs) inhibit gene expression, by cleavage and destruction of specific mRNA molecules. Use of Small Interfering RNA (siRNA) is a novel method in the induction of RNA Interference (RNAi), which is a potent method for therapeutics of allergic reactions. Due to various effects of STAT 6 proteins during hypersensitivity reactions caused by pollen allergens, mRNA of STAT6 gene is selected as target gene for allergy therapeutics via Post-Transcriptional Gene Silencing (PTGS). Using molecular docking study a specific sense siRNA is identified as anti allergic drug to treat allergic asthma during immediate type of hypersensitivity reaction, caused by Zea m 1 pollen allergen.
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Sonawane, Kailas Dashrath, and Maruti Jayram Dhanavade. "Molecular Docking Technique to Understand Enzyme-Ligand Interactions." In Methods and Algorithms for Molecular Docking-Based Drug Design and Discovery, 246–66. IGI Global, 2016. http://dx.doi.org/10.4018/978-1-5225-0115-2.ch010.
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Molecular docking has advanced to such an extent that one can rapidly and accurately identify pharmaceutically useful lead compounds. It is being used routinely to understand molecular interactions between enzyme and ligand molecules. Several computational approaches are combined with experimental work to investigate molecular mechanisms in detail at the atomic level. Molecular docking method is also useful to investigate proper orientation and interactions between receptor and ligand. In this chapter we have discussed protein-protein approach to understand interactions between enzyme and amyloid beta (Aß) peptide. The Aß peptide is a causative agent of Alzheimer's disease. The Aß peptides can be cleaved specifically by several enzymes. Their interactions with Aß peptide and specific enzyme can be investigated using molecular docking. Thus, the molecular information obtained from docking studies might be useful to design new therapeutic approaches in treatment of Alzheimer's as well as several other diseases.
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Kashif, Mohd, Mohammad Waseem, Poornima D. Vijendra, and Ashok Kumar Pandurangan. "Protective Effects of Cannabis in Neuroinflammation-Mediated Alzheimer's Disease." In Medical Cannabis and the Effects of Cannabinoids on Fighting Cancer, Multiple Sclerosis, Epilepsy, Parkinson's, and Other Neurodegenerative Diseases, 48–75. IGI Global, 2022. http://dx.doi.org/10.4018/978-1-6684-5652-1.ch002.
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In recent years, Alzheimer's disease (AD) has been recognized as an age-related neurological disorder wherein neurons degenerate and exhibit abnormal structure and function. Aging is the primary factor in the progression of AD from mild to severe cognitive impairment. No effective targeted therapies are presently available, and treatment is limited to symptomatic management. The neuropathologic hallmarks of the disease include the accumulation of amyloid-beta (Aβ) plaques in brain tissues and the aggregation of hyperphosphorylated-tau proteins (tangles) within neurons. Associated hyperactivation of neuroinflammation results in release of inflammatory molecules from neurons, microglia, and astrocytes, which have been linked with neuronal loss and the worsening neurodegeneration. The anti-inflammatory and neuroprotective properties of cannabis-based medicines may offer benefits in delaying the progression of neurodegenerative diseases including AD. This chapter explores the role of cannabinoids in countering neuroinflammation-mediated AD pathology.
Conference papers on the topic "Beta - Lactam Based Molecules"
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Perminova, Irina. "Humics-Based Chemicals and Materials Designed for Ecoadaptive Chemistry and Technology." In 20TH CONFERENCE OF THE INTERNATIONAL HUMIC SUBSTANCES SOCIETY. Non-Commercial Partnership "Center for Biogenic Resources "Humus Sapiens" (NP CBR "Humus Sapiens"), 2021. http://dx.doi.org/10.36291/ihss.2021.perminova.
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Humic substances (HS) are abundant in the environment. They penetrate through water, soil, and air. They have plentiful fossil and renewable resources including oxidized brown coal, peat, sapropel, spent sulphite liquor, composts, and other organic waste. HS govern many vitally important ecosystem processes like maintenance of soil fertility, nutrients delivery to plants, mitigation of abiotic stresses, etc. Numerous examples on their beneficial effects to plants and other living organisms are reported. Still, due to complexity of humic molecular assemblies, they have been very limitedly tapped for practical needs. Here we introduce a concept of ecoadaptive chemistry, which implies molecular and functional studies of life-sustaining processes in nature aimed at their further transfer into ecoadaptive technologies via rational design of nature-like chemicals, materials, and processes (Perminova 2019). We show how the disclosed mechanisms of self-purification and self-healing implied by natural systems can be applied to molecular design of humics-based products (chemicals, materials) with the tailored properties. The examples will be given for direct chemical modification of HS by incorporation of phenolic units into molecular backbone of HS, for preparation of interpolyelectrolyte complexes with aminoorganolanes , for HS assisted synthesis of nanoparticles with the needed properties (iron (hydr)oxides, silver, gold), for preparation of HS-based hybrid nanomaterials. The possibilities for practical applications of the obtained humic derivatives, polyelectrolyte complexes, HS-stabilized nanoparticles and hybrid materials will be demonstrated. They include novel humics-based biocatalytic systems for manipulation of microbial metabolism (suppression of methane synthesis by methanogens), solid HS-clay emulsion stabilizers for eliminating of oil slicks, humics-based non-lactam inhibitors of beta-lactamases, HS-based nanomaterials for wound-healing. The developed approaches open a way for broad innovative applications of humics-based chemicals and materials both in the field of environmental protection, biotechnology, human and environmental health. They also contribute to further elaboration and development of the concept of ecoadaptive chemistry and technology. References Perminova, I.V. From green chemistry and nature-like technologies towards ecoadaptive chemistry and technology. Pure and Applied Chemistry 2019, 91(5), 851-864. DOI: 10.1515/pac2018-1110 Acknowledgement: This research was supported by the Russian Science Foundation 20-63- 47070. The studies were conducted in the framework of the Interdisciplinary Scientific and Educational School of M. V. Lomonosov Moscow State University “Future Planet and Global Environ-mental Change”.
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"Molecular composition - inhibition activity relationships for humic substances narrow fractions sets obtained by solid-phase extraction." In Sixth International Conference on Humic Innovative Technologies "Humic Substances and Eco-Adaptive Technologies ”(HIT – 2021). Non-Commercial Partnership "Center for Biogenic Resources "Humus Sapiens" (NP CBR "Humus Sapiens"), 2021. http://dx.doi.org/10.36291/hit.2021.mikhnevich.001.
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Humic substances (HS) have a wide spectrum of biological activity including inhibitory activity against β-lactamases.1 The latter are capable of hydrolyzing beta-lactam antibiotics and represent one of the main pathways of bacterial antibiotic resistance. HS are characterized by low toxicity and good solubility in water. A use of HS for therapeutic purposes is hindered by extreme molecular heterogeneity and high level of isomeric complexity. Solid-phase extraction (SPE) fractionation in combination with ultra-high resolution mass spectrometry (FTICR MS) is a promising method to simplify this molecular system and isolate the most active components of HS. The aim of this work was to test various SPE fractionation schemes as an approach to directed isolation of the components with the given activity from HS. The sample of coal humic acids (CHA-G) was isolated from the commercial sodium humate “Genesis” and separated using SPE cartridge according to gradients in polarity1 and acidity2 inherent within the molecular components of HS. Inhibitory activity against β- lactamase TEM-1 and its mutants was measured using chromogenic substrate CENTA. Molecular composition of fractions was determined using FTICR mass spectrometer 15 T solariX (Bruker Daltonics) located at the Collective Use Center of Zelinsky Institute of Organic Chemistry of RAS. Molecular assignments were plotted into van Krevelen diagrams. The diagrams were binned into 20 cells are assigned to seven chemotypes, and occupational densities for each chemotype were calculated after Perminova.3 For the fractions separated by polarity, a substantial difference in the molecular composition was observed. Inhibitory activity grew along with an increase in hydrophobicity. The HS activity increased along with an increase in contribution of condensed tannins and phenylisopropanoids (O/C <0.5, H/C <1.4) and decreased along with contribution of hydrolyzed tannins (O/C> 0.5, H/C <1.4). The similar analysis was conducted for the fractions separated with regard to pKa value of the dominating functional groups. The most isomeric complex molecular components were defined, which can be found in different HS fractions, but they are identical in elemental composition. The data obtained make it possible to choose the most efficient fractionation method that effectively lowers the molecular complexity of HS and makes it possible to isolate the most active HS fractions. SPE-fractionation in combination with 2D chromatography is going to be used in our future studies to achieve high resolution separation and more reliable “molecular composition-activity” relationships. Further research might bring substantial advance in the field of directed design of biologically active humic-based materials and compositions. Acknowledgements. This work was supported by the grant of the Russian Science Foundation no 21-73-20202. The center of collective use of the Zelinsky IOC RAS is appreciated. The research was conducted in the framework of the Scientific-Educational School of the Lomonosov MSU “Future of the plant and global environmental change”. References 1. Mikhnevich et al., ACS Omega, 2021, https://doi.org/10.1021/acsomega.1c02841 2. Zherebker et al., Environ. Sci. Technol. 2020, 54, 2667−2677 3. Perminova, I. V. PAC, 2019, 91(5), 851
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Hanna, Sherif F., Rodolfo Barron-Jimenez, Thomas N. Anderson, Robert P. Lucht, Thomas Walther, and Jerald A. Caton. "Diode-Laser-Based Ultraviolet Absorption Sensor for NO." In Laser Applications to Chemical and Environmental Analysis. Washington, D.C.: Optica Publishing Group, 2002. http://dx.doi.org/10.1364/lacea.2002.pd5.
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We have developed a new diode-laser-based sensor system for ultraviolet absorption measurements of the NO molecule. The laser system is illustrated schematically in Fig. 1. This system is based on sum-frequency-mixing (SFM) of a tunable, 395-nm external-cavity diode laser (ECDL) from Toptica Lasers with a frequency-doubled, diode-pumped Nd:YAG laser (CrystaLaser) in a beta barium borate (BBO) crystal. Because of the strength of the ultraviolet A2Σ+ - X2∏ electronic transition of NO, the detection limit of the system is approximately 0.1 ppm of NO per meter of path length. In addition, the simplicity, generality, and relatively low cost of the SFM-based sensor strategy discussed in this paper will enable the development of absorption sensors throughout the entire ultraviolet spectrum, opening up a wide range of new possibilities for sensing and control of chemically reacting flow processes.
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Hagen, Alexander R., Thomas F. Grimes, Brian C. Archambault, Trevor N. Harris, and Rusi P. Taleyarkhan. "Characterization and Optimization of a Tensioned Metastable Fluid Nuclear Particle Sensor Using Laser Based Profilimetry." In 2014 22nd International Conference on Nuclear Engineering. American Society of Mechanical Engineers, 2014. http://dx.doi.org/10.1115/icone22-30325.
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State of the art neutron detectors lack capabilities required by the fields of homeland security, health physics, and even for direct in-core nuclear power monitoring. A new system being developed at Purdue’s Metastable Fluid and Advanced Research Laboratory in conjunction with S/A Labs, LLC provides capabilities the state of the art lacks, and simultaneously with beta (β) and gamma (γ) blindness, high (> 90% intrinsic) efficiency for neutron/alpha spectroscopy and directionality, simple detection mechanism, and lowered electronic component dependence. This system, the Tensioned Metastable Fluid Detector (TMFD) [3], provides these capabilities despite its vastly reduced cost and complexity compared with equivalent present day systems. Fluids may be placed at pressures lower than perfect vacuum (i.e. negative) [4, 5], resulting in tensioned metastable states. These states may be induced by tensioning fluids just as one would tension solids. The TMFD works by cavitation nucleation of bubbles resulting from energy deposited by charged ions or laser photon pileup heating of fluid molecules which are placed under sufficiently tensioned (negative) pressure states of metastability. The charged ions may be created from neutron scattering, or from energetic charged particles such as alphas, alpha recoils, fission fragments, etc. A methodology has been created to profile the pressures in these chambers by lasing, called Laser Induced Cavitation (LIC), for verification of a multiphysics simulation of the chambers. The methodology and simulation together have lead to large efficiency gains in the current Acoustically Tensioned Metastable Fluid Detector (ATMFD) system. This paper describes in detail the LIC methodology and provides background on the simulation it validates.
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Plow, E. F., G. A. Marguerie, and M. H. Ginsberg. "RECOGNITION SPECIFICITY OFADHESION RECEPTORS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643728.
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The cytoadhesins are a broadly distributedfamily of structurally, immunologicallyand functionally related cell surface molecules which participate in cellular adhesivereactions. The members of this family are heterodimeric in structure and consist of similar, if not identical, beta subunitsand related, but not identical, alpha subunits. A common functional property of the cytoadhesins is that they possess an arginyl-glycyl-aspartic acid (RGD) recognition specificity which mediates their capacity to act as receptors for adhesive proteins.The above assigned characteristics of thecytoadhesin family are based upon immunochemical analyses, primary structural determinations, deduced amino acid sequences fromcDNA clones and from dissectionof the recognition specificity of specificfamily members for their adhesive proteins.Platelet GPIIb-IIIa, the prototype of thecytoadhesin family, exhibits a very relaxed recognition specificity which permits itto interact with at least four distinct RGD-containing proteins: fibrinogen (Fg), fibronectin, von Willebrand Factor and vitronectin. RGD-containing peptidesas well as peptides corresponding in structure to the extreme carboxyl terminus of the gamma chain of Fg inhibit the binding of this adhesive protein set to GPIIb-IIIa.Both peptide sets interact with GPIIb-IIIaat either the same set of sites or intercommunicating sites. Nevertheless, using crosslinking reagents, certain RGD and gamma chain peptides can be crosslinked to different subunits of GPIIb-IIIa. This raises the possibility that a binding pocket for the adhesive proteins on GPIIb-IIIa may be directly comprised or situated in close proximity to both subunits of the cytoadhesin. Endothelial cells also express a cytoadhesin which is capable of binding Fg. Although both RGD and gamma chain peptides inhibit this interaction, the finerecognition specificity of the platelet and endothelial cell cytoadhesin for Fg are distinguishable. Thus, by combining very similar if not the same beta subunits with different alpha subunits, the RGD specificity of the cytoadhesins may bemodulated to achieve selectivity in the recognition of adhesive proteins.
Reports on the topic "Beta - Lactam Based Molecules"
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Chiu, Chia-Yu, and Amara Sarwal. Impact of area under the curve-based vancomycin dosing combination with anti-pseudomonal beta-lactam antibiotics: a systematic review and meta-analysis. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, December 2022. http://dx.doi.org/10.37766/inplasy2022.12.0025.
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Review question / Objective: Did AUC-based vancomycin dosing reduce acute kidney injury than trough-based dosing when combined with anti-pseudomonal beta-lactam antibiotic? Condition being studied: Patients received Vancomycin combined with anti-pseudomonal beta-lactam antibiotics and monitor with either trough-base dosing or AUC-based dosing vancomycin. Information sources: All study types except case reports, case series, and conference abstracts were considered. PubMed, Embase, Cochrane Library, and ClinicalTrials.gov were searched from inception to November2022.