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Bai, Yuchen, Leina Dou, Weilin Wu, Zhimin Lu, Jiaqian Kou, Jianzhong Shen, Kai Wen i Zhanhui Wang. "Anti-Metatype Antibody Screening, Sandwich Immunoassay Development, and Structural Insights for β-Lactams Based on Penicillin Binding Protein". Molecules 26, nr 18 (13.09.2021): 5569. http://dx.doi.org/10.3390/molecules26185569.
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Theoretically, sandwich immunoassay is more sensitive and has a wider working range than that of competitive format. However, it has been thought that small molecules cannot be detected by the sandwich format due to their limited size. In the present study, we proposed a novel strategy for achieving sandwich immunoassay of β-lactams with low molecular weights. Firstly, five β-lactam antibiotics were selected to bind with penicillin binding protein (PBP)2x* to form complexes. Then, monoclonal and polyclonal antibodies against PBP2x*-β-lactams complexes were produced by animal immunization. Subsequently, the optimal pairing antibodies were utilized to establish sandwich immunoassay for detection of 18 PBP2x*-β-lactam complexes. Among them, ceftriaxone could be detected at as low as 1.65 ng/mL with working range of 1–1000 ng/mL in milk. To reveal the detection mechanism, computational chemistry and molecular recognition study were carried out. The results showed that β-lactams with a large size and complex structures maybe conducive to induce conformational changes of PBP2x*, and then exhibit greater possibility of being detected by sandwich immunoassay after combination with PBP2x*. This study provides insights for subsequent investigations of anti-metatype antibody screening and sandwich immunoassay establishment for small-molecule detection.
2
Becker, D., M. Botoshansky, N. Gasper, F. H. Herbstein i M. Karni. "2-Phenyl-4-hydroxyphthalazin-1-one: A Benzoannelated Derivative of Maleic Hydrazide". Acta Crystallographica Section B Structural Science 54, nr 5 (1.10.1998): 671–76. http://dx.doi.org/10.1107/s0108768197015760.
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The monoclinic crystals (space group P21/a, Z = 8) of 2-phenyl-4-hydroxyphthalazin-1-one, C14H10N2O2, have two independent molecules (A and B) in the asymmetric unit. Both occur as the lactim–lactam (hydroxy–one) structure, which is also found in the parent molecule maleic hydrazide (both triclinic and monoclinic polymorphs), dichloromaleic hydrazide and luminol (3-aminophthalhydrazide). The molecular arrangement is based on strings of alternating A and B molecules linked by hydroxyl...carbonyl hydrogen bonds, with only van der Waals interactions between adjacent strings. Comparison is made of the measured bond lengths for (monoclinic) maleic hydrazide and values from high-level ab initio calculations, and reasonably good agreement is obtained, with indications of improvements when allowance is made for electron correlation and hydrogen bonding.
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Cox, Robin A. "Lactams in sulfuric acid. The mechanism of amide hydrolysis in weak to moderately strong aqueous mineral acid media". Canadian Journal of Chemistry 76, nr 6 (1.06.1998): 649–56. http://dx.doi.org/10.1139/v98-012.
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Reaction rate constants obtained in moderately concentrated sulfuric acid for the hydrolysis of simple lactams of ring sizes five, six, seven, and eight as a function of acidity and temperature have been analyzed using the excess acidity kinetic method. The basicity constants for these substrates have been recalculated; the 13C NMR spectra used to obtain these values are very sensitive to medium effects. It was found that the basicities of the lactams at 0.003-0.1 M lactam concentration were over half a pK unit more basic than they were at 0.5 M lactam, presumably because of the medium effect. Apart from this, the rate constant results obtained at different times by different groups using different techniques for monitoring the kinetics are in adequate agreement. The excess acidity analysis showed that the kinetics could be fitted according to the "three-water-molecule followed by one-water-molecule" mechanistic scenario previously found, or could just as well be fitted by a "one-water-molecule followed by unknown mechanism" scenario, with the mechanistic change taking place at 50 wt.% sulfuric acid for all the substrates. Other evidence makes the latter seem the more likely possibility of the two, and activation parameters based upon the "one-water-molecule" process were determined. Sufficient data points to enable the unknown mechanism to be established were not present; possible mechanisms applicable in media more concentrated than 50 wt.% sulfuric acid are discussed. Previously obtained values of the parameter r, the number of water molecules involved with the substrate in A2 processes, are now questionable.Key words: amides, lactams, excess acidity, hydrolysis, mechanism.
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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 i Leonardo C. Pacheco-Londoño. "Docking and Molecular Dynamic of Microalgae Compounds as Potential Inhibitors of Beta-Lactamase". International Journal of Molecular Sciences 23, nr 3 (31.01.2022): 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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Twamley, Brendan, Niamh M. O'Boyle i Mary J. Meegan. "Azetidin-2-ones: structures of antimitotic compounds based on the 1-(3,4,5-trimethoxyphenyl)azetidin-2-one core". Acta Crystallographica Section E Crystallographic Communications 76, nr 8 (3.07.2020): 1187–94. http://dx.doi.org/10.1107/s2056989020008555.
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A series of related substituted 1-(3,4,5-trimethoxyphenyl)azetidin-2-ones have been characterized: 3-(4-fluorophenyl)-4-(4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one, C25H24FNO5 (1), 3-(furan-2-yl)-4-(4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one, C23H23NO6 (2), 4-(4-methoxyphenyl)-3-(naphthalen-1-yl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one, C29H27NO5 (3), 3-(3,4-dimethoxyphenyl)-4-(4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one, C27H29NO7 (4) and 4,4-bis(4-methoxyphenyl)-3-phenyl-1-(3,4,5-trimethoxyphenyl)azetidin-2-one, C32H31NO6 (5). All of the compounds are racemic. The lactam and 3,4,5-trimethoxyphenyl rings are approximately co-planar and the orientation of the lactam and the 4-methoxyphenyl substituent is approximately orthogonal. The chiral centres, although eclipsed by geometry, have torsion angles ranging from −7.27 to 13.08° for the 3 position, and −8.69 to 13.76° for the 4 position of the β-lactam. The structures display intramolecular C—H...O bonding between the 3,4,5-trimethoxyphenyl ring and the lactam ketone. Further C—H...O interactions are observed and form either an opposing methoxy `buckle' to join two molecules together or a cyclic dimer.
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Shiri, Pezhman. "Novel Hybrid Molecules Based on triazole-β-lactam as Potential Biological Agents". Mini-Reviews in Medicinal Chemistry 21, nr 5 (2021): 536–53. http://dx.doi.org/10.2174/18755607mtewaotyn5.
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Molteni, Elena, Giovanni Onida, Matteo Ceccarelli i Giancarlo Cappellini. "Ab Initio Spectroscopic Investigation of Pharmacologically Relevant Chiral Molecules: The Cases of Avibactam, Cephems, and Idelalisib as Benchmarks for Antibiotics and Anticancer Drugs". Symmetry 13, nr 4 (3.04.2021): 601. http://dx.doi.org/10.3390/sym13040601.
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The ability to accurately measure or predict several physicochemical properties of molecules which play a role as active substances in drugs can be of strategic importance for pharmacological applications, in addition to its possible interest in fundamental research. Chirality is a relevant feature in the characterization of drug molecules: enantiomers can show different pharmacological activity and adverse effects. The ability to separate stereoisomers and to assign their absolute configuration can thus be crucial. Circular dichroism (CD) spectra are a useful tool to distinguish between enantiomers. In this work we apply an in-house developed code, based on an efficient DFT approach for circular dichroism, to fully characterize the molecular optical properties in the case of few selected fundamental molecules for current medical and pharmaceutical research, namely avibactam, as representative of non β-lactam inhibitors, two cephems (cefepime and cefoxitin), as examples of β-lactam antibiotics, and idelalisib, as a recent relevant anticancer active substance to treat major leukemias. For the above molecules, in addition to their optical absorption spectra, we calculate their CD spectra within state-of-the-art computational techniques. We then investigate both the conformational and chemical sensitivity of absorption and CD spectra for the chosen molecules. The outcomes of the present research could be of fundamental importance to gain additional information on molecules involved in therapeutic protocols for severe diseases or in drug design.
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Kurmaz, Svetlana V., Natalia V. Fadeeva, Vladislav M. Ignat’ev, Vladimir A. Kurmaz, Sergei A. Kurochkin i Nina S. Emel’yanova. "Structure and State of Water in Branched N-Vinylpyrrolidone Copolymers as Carriers of a Hydrophilic Biologically Active Compound". Molecules 25, nr 24 (18.12.2020): 6015. http://dx.doi.org/10.3390/molecules25246015.
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Hydrated copolymers of N-vinylpyrrolidone (VP) with triethylene glycol dimethacrylate as a promising platform for biologically active compounds (BAC) were investigated by different physical chemical methods (dynamic light scattering, infrared spectroscopy, thermal gravimetric analysis, and differential scanning calorimetry) and the quantum chemical modeling of water coordination by the copolymers in a solution. According to the quantum chemical simulation, one to two water molecules can coordinate on one O-atom of the lactam ring of VP units in the copolymer. Besides the usual terminal coordination, the water molecule can form bridges to bind two adjacent C=O groups of the lactam rings of VP units. In addition to the first hydration shell, the formation of a second one is also possible due to the chain addition of water molecules, and its structure depends on a mutual orientation of C=O groups. We showed that N,N-dimethylbiguanidine hydrochloride (metformin) as a frontline drug for the treatment of type 2 diabetes mellitus can be associated in aqueous solutions with free and hydrated C=O groups of the lactam rings of VP units in studied copolymers. Based on the characteristics of the H-bonds, we believe that the level of the copolymer hydration does not affect the behavior and biological activity of this drug, but the binding of metformin with the amphiphilic copolymer will delight in the penetration of a hydrophilic drug across a cell membrane to increase its bioavailability.
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Shlaes, D. M., i C. Currie-McCumber. "Mutations altering substrate specificity in OHIO-1, and SHV-1 family β-lactamase". Biochemical Journal 284, nr 2 (1.06.1992): 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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Maity, Arindam, Sarmi Sardar, Shilpa Chatterjee, Nripendra Nath Bala, Sudhan Debnath i Debanjan Sen. "De-Novo Design of Hits Against New Delhi Metallo-β-Lactamase Enzyme". International Journal of Quantitative Structure-Property Relationships 7, nr 2 (kwiecień 2022): 1–13. http://dx.doi.org/10.4018/ijqspr.290010.
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The New Delhi Metallo-β-lactamase 1 (NDM-1) is a class of Metallo-β lactamase enzyme. It is responsible for hydrolyzing almost all β-lactam antibiotics, leading to multi-drug resistance in bacteria. The lack of specific therapeutic options against this target creates an emerging need to develop new molecules against it. The multistep fragment- and knowledge-based de-novo design methods were considered for this study to design small molecules. The designed molecules were evaluated by molecular docking and dynamics simulation, followed by drug-likeness prediction. This study reports that a new drug-like chemical entity exhibits good binding behavior against the MDM-1 enzyme. Nonetheless, in-depth biological evaluation is required to determine the efficacy of the designed binders to develop new therapeutics against NDM-1.
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Khalesi, Maryam, Azim Ziyaei Halimehjani i Jürgen Martens. "Synthesis of a novel category of pseudo-peptides using an Ugi three-component reaction of levulinic acid as bifunctional substrate, amines, and amino acid-based isocyanides". Beilstein Journal of Organic Chemistry 15 (4.04.2019): 852–57. http://dx.doi.org/10.3762/bjoc.15.82.
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The synthesis of a novel category of pseudo-peptides via intramolecular Ugi reaction of levulinic acid (4-oxopentanoic acid), aromatic and aliphatic amines, and amino acid-based isocyanides is reported. Levulinic acid was applied as a bifunctional substrate containing both carbonyl and acid moieties suitable for the Ugi reaction. This article provides a facile and convenient one-pot procedure for the synthesis of peptide-like heterocyclic molecules containing 2-pyrrolidone (γ-lactam), amide and ester functional groups with good to excellent yields.
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Abdullah, Shahla M., i Shwan Rachid. "On Column Binding a Real-Time Biosensor for β-lactam Antibiotics Quantification". Molecules 25, nr 5 (10.03.2020): 1248. http://dx.doi.org/10.3390/molecules25051248.
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This work aimed to develop accurate, quick, and practical tools for the detection of residues of penicillin G antibiotic in biological and non-biological samples. The assays were developed based on the binding mechanism of β-lactam to penicillin-binding proteins; samples of different concentrations of penicillin G were incubated with in vitro expressed 6X-Histidine-tagged soluble penicillin-binding protein (PBP2x*) of Streptococcus pneumoniae (S. pneumoniae), whereby penicillin G in samples specifically binds to PBP2x*. The fluorescent-labeled β-lactam analogue Bocillin FL was used as a competent substrate, and two different routes estimated the amounts of the penicillin G. The first route was established based on the differences in the concentration of non-bounded Bocillin FL molecules within the reactions while using a real-time polymerase chain reaction (PCR)-based method for fluorescence detection. The second route depended on the amount of the relative intensity of Bocillin FL bounded to Soluble PBP-2x*, being run on sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-page), visualized by a ChemiDoc-It®2 Imager, and quantified based on the fluorescence affinity of the competent substrate. While both of the methods gave a broad range of linearity and high sensitivity, the on column based real-time method is fast, non-time consuming, and highly sensitive. The method identified traces of antibiotic in the range 0.01–0.2 nM in addition to higher accuracy in comparison to the SDS-based detection method, while the sensitivity of the SDS-based method ranged between 0.015 and 2 µM). Thus, the on column based real time assay is a fast novel method, which was developed for the first time based on the binding inhibition of a fluorescence competitor material and it can be adapted to screen traces of penicillin G in any biological and environmental samples.
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Minhas, Gurdeep S., i Simon Newstead. "Structural basis for prodrug recognition by the SLC15 family of proton-coupled peptide transporters". Proceedings of the National Academy of Sciences 116, nr 3 (2.01.2019): 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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Lánská, B., L. Matisová-Rychlá, J. Broz̆ek i J. Rychlý. "Chemiluminescence of polyamides II. Luminescence accompanying thermooxidation of lactam-based polyamides related to the content of end-groups of molecules". Polymer Degradation and Stability 66, nr 3 (grudzień 1999): 433–44. http://dx.doi.org/10.1016/s0141-3910(99)00096-8.
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Chepak, Aleksandr, Denis Balatskiy, Mikhail Tutov, Aleksandr Mironenko i Svetlana Bratskaya. "Light Harvesting Nanoprobe for Trace Detection of Hg2+ in Water". Molecules 28, nr 4 (8.02.2023): 1633. http://dx.doi.org/10.3390/molecules28041633.
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The continuously increasing flow of toxic heavy metals to the environment due to intensive industrial activity and tightening requirements with regard to the content of metal ions in drinking and discharged waters urges the development of affordable and sensitive devices to the field control of pollutants. Here, we report a new thiated Rhodamine-lactam probe for Hg2+ detection and demonstrate how its sensitivity can be increased via the incorporation of the probe molecules into the optically transparent siloxane-acrylate coatings on polymethyl methacrylate and, alternatively, into the water-dispersible light-harvesting FRET nanoparticles (NPs), in which dye cations are separated by fluorinated tetraphenylborate anions. We have shown that the optimization of the FRET NPs composition had allowed it to reach the antenna effect of ~300 and fabricate “off/on” sensor for Hg2+ ion determination in aqueous solutions with the detection limit of ~100 pM, which is far below the maximum permissible concentration (MPC) of mercury in drinking water recommended by the World Health Organization. Although this work is more proof-of-concept than a ready-to-use analytical procedure, the suggested approaches to fabrication of the FRET NPs based on the popular rhodamine-lactam platform can be used as a background for the development of low-cost portable sensing devices for the extra-laboratory determination of hazardous metal ions.
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Zarganes-Tzitzikas, Tryfon, Gonçalo Clemente, Philip Elsinga i Alexander Dömling. "MCR Scaffolds Get Hotter with 18F-Labeling". Molecules 24, nr 7 (4.04.2019): 1327. http://dx.doi.org/10.3390/molecules24071327.
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Imaging techniques, such as positron emission tomography (PET), represent great progress in the clinical development of drugs and diagnostics. However, the efficient and timely synthesis of appropriately labeled compounds is a largely unsolved problem. Numerous small drug-like molecules with high structural diversity can be synthesized via convergent multicomponent reactions (MCRs). The combination of PET labeling with MCR synthesis of biologically active compounds can greatly simplify radioanalytical and imaging-based analysis. In a proof-of-concept study, we optimized robust on-site radiolabeling conditions that were subsequently applied to several structurally different drug-like MCR scaffolds (e.g., arenes, β-lactam, tetrazole, and oxazole). These labeled scaffolds were synthesized via pinacol-derived aryl boronic esters (arylBPin) by copper-mediated oxidative 18F-fluorination with radiochemical conversions (RCCs) from 15% to 76%.
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Presnova, Galina V., Denis E. Presnov, Anna A. Filippova, Ilia I. Tsiniaikin, Mariya M. Ulyashova i Maya Yu Rubtsova. "Multiplex Digital Quantification of β-Lactamase Genes in Antibiotic-Resistant Bacteria by Counting Gold Nanoparticle Labels on Silicon Microchips". Biosensors 12, nr 4 (9.04.2022): 226. http://dx.doi.org/10.3390/bios12040226.
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Digital quantification based on counting of individual molecules is a promising approach for different biomedical applications due to its enhanced sensitivity. Here, we present a method for the digital detection of nucleic acids (DNA and RNA) on silicon microchips based on the counting of gold nanoparticles (GNPs) in DNA duplexes by scanning electron microscopy (SEM). Biotin-labeled DNA is hybridized with capture oligonucleotide probes immobilized on the microchips. Then biotin is revealed by a streptavidin–GNP conjugate followed by the detection of GNPs. Sharp images of each nanoparticle allow the visualization of hybridization results on a single-molecule level. The technique was shown to provide highly sensitive quantification of both short oligonucleotide and long double-strand DNA sequences up to 800 bp. The lowest limit of detection of 0.04 pM was determined for short 19-mer oligonucleotide. The method’s applicability was demonstrated for the multiplex quantification of several β-lactamase genes responsible for the development of bacterial resistance against β-lactam antibiotics. Determination of nucleic acids is effective for both specific DNA in lysates and mRNA in transcripts. The method is also characterized by high selectivity for single-nucleotide polymorphism discrimination. The proposed principle of digital quantification is a perspective for studying the mechanisms of bacterial antibiotic resistance and bacterial response to drugs.
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Maham Khan, Shahid Wahab, Haroon Muhammad Ali, Sadia Khan, Reema Iqbal i Tariq Khan. "Biogenic Nanomaterials: A Way Forward in Preventing Bacterial Infections". Proceedings of the Pakistan Academy of Sciences: B. Life and Environmental Sciences 60, S (22.01.2023): 3–23. http://dx.doi.org/10.53560/ppasb(60-sp1)814.
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Antibiotic resistance puts a tremendous strain on the healthcare system. Bacteria such as Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas aeruginosa that cause diseases like endocarditis, pneumonia, and Urinary tract infections have now become resistant to many previously used antibiotics. Antibiotic overuse must be reduced as it has become a public health threat paving the way to pandemics. Instead of creating new antibiotics, repurposing existing medicines that have faced resistance is one way forward. Plant-based antimicrobials have been explored as antibiotics to boost or augment the capability of existing antibiotics. It has been proposed that conjugates of plant-based products and antibiotics have increased activity and that the conjugated groups could help circumvent the beta-lactam antibiotic resistance mechanisms. Antibiotics have been combined with plant-based substances like Berberine, and a considerable synergy has been reported among them. Nanomaterials also promise a powerful environment-friendly strategy for weaponizing antibiotics with plant compounds. Nanoparticles could attach with many biological molecules such as DNA, enzymes, ribosomes, and lysosomes, further affecting the permeability of the cell membrane. The interaction of nanoparticles with many biological targets makes it hard for bacteria to develop resistance against them. Low molecular weight nanomaterial based on antibiotics could be very effective against multidrug-resistant gram-negative pathogens. Our study aims to analyze the progress done at the front of nanomaterials and nano-antibiotics against infectious diseases.
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Aslanli, Aysel, Ilya Lyagin i Elena Efremenko. "Novel approach to quorum quenching: rational design of antibacterials in combination with hexahistidine-tagged organophosphorus hydrolase". Biological Chemistry 399, nr 8 (26.07.2018): 869–79. http://dx.doi.org/10.1515/hsz-2018-0162.
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Abstract N-acyl homoserine lactones (AHLs) are quorum sensing (QS) signal molecules used by most Gram-negative pathogenic bacteria. In this article the lactonase activity of the preparations based on hexahistidine-tagged organophosphorus hydrolase (His6-OPH) towards AHLs was studied. Initially, three of the most interesting β-lactam antibiotics were selected from seven that were trialed during molecular docking to His6-OPH. Combinations of antibiotics (meropenem, imipenem, ceftriaxone) and His6-OPH taken in the native form or in the form of non-covalent enzyme-polyelectrolyte complexes (EPCs) with poly(glutamic acid) or poly(aspartic acid) were obtained and investigated. The lactonase activity of the preparations was investigated under different physical-chemical conditions in the hydrolysis of AHLs [N-butyryl-D,L-homoserine lactone, N-(3-oxooctanoyl)-D,L-homoserine lactone, N-(3-oxododecanoyl)-L-homoserine lactone]. An increased efficiency of catalytic action and stability of the lactonase activity of His6-OPH was shown for its complexes with antibiotics and was confirmed in trials with bacterial strains. The broadening of the catalytic action of the enzyme against AHLs was revealed in the presence of the meropenem. Results of molecular docking of AHLs to the surface of the His6-OPH dimer in the presence of antibiotics allowed proposing the mechanism of such interference based on a steric repulsion of the carbon chain of hydrolyzed AHLs by the antibiotics bounded to the enzyme surface.
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Gaudêncio, Susana P., i Florbela Pereira. "Predicting Antifouling Activity and Acetylcholinesterase Inhibition of Marine-Derived Compounds Using a Computer-Aided Drug Design Approach". Marine Drugs 20, nr 2 (8.02.2022): 129. http://dx.doi.org/10.3390/md20020129.
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Biofouling is the undesirable growth of micro- and macro-organisms on artificial water-immersed surfaces, which results in high costs for the prevention and maintenance of this process (billion €/year) for aquaculture, shipping and other industries that rely on coastal and off-shore infrastructure. To date, there are still no sustainable, economical and environmentally safe solutions to overcome this challenging phenomenon. A computer-aided drug design (CADD) approach comprising ligand- and structure-based methods was explored for predicting the antifouling activities of marine natural products (MNPs). In the CADD ligand-based method, 141 organic molecules extracted from the ChEMBL database and literature with antifouling screening data were used to build the quantitative structure–activity relationship (QSAR) classification model. An overall predictive accuracy score of up to 71% was achieved with the best QSAR model for external and internal validation using test and training sets. A virtual screening campaign of 14,492 MNPs from Encinar’s website and 14 MNPs that are currently in the clinical pipeline was also carried out using the best QSAR model developed. In the CADD structure-based approach, the 125 MNPs that were selected by the QSAR approach were used in molecular docking experiments against the acetylcholinesterase enzyme. Overall, 16 MNPs were proposed as the most promising marine drug-like leads as antifouling agents, e.g., macrocyclic lactam, macrocyclic alkaloids, indole and pyridine derivatives.
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Kamat, Shweta, Pankaj Gupta i Akshata Mane. "2288. Role of Β Lactam-Β Lactamase Inhibitors in Indian Tertiary Care Hospitals: Results from a Nationwide Survey". Open Forum Infectious Diseases 6, Supplement_2 (październik 2019): S784. http://dx.doi.org/10.1093/ofid/ofz360.1966.
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Abstract Background Broad-spectrum antibiotics, particularly third-generation cephalosporins, are routinely used in the treatment of nosocomial infections. The emergence of Extended Spectrum Β-Lactamase (ESBL)-producing pathogens in Indian tertiary care hospitals warrants the need to reassess β-lactam–β-lactamase inhibitors (BL-BLIs) as better alternative treatments. Methods An online survey was conducted by Pfizer India to understand the usage of BL-BLIs across Indian hospitals. The survey was administered to 334 clinicians across multiple specialties out of which 195 were from tertiary care hospitals. Results were analyzed using MS-Excel statistical tools. Results One-hundred ninety-five (195) clinicians from tertiary care hospitals completed the survey. About 78% of HCPs revealed the resistance to third-generation cephalosporins (e.g., ceftriaxone, ceftazidime) to be between 10–60% in their clinical settings. BL-BLIs were mostly preferred for treatment based on hospital antibiograms (64%) and used as first-line options for hospitalized adults with mild-moderate severe infections caused by ESBL-producing organisms (71%) and in mild-moderate infections caused by susceptible Gram-negative bacteria such as Enterobacteriaceae (54%). The average duration of IV BL-BLI treatment was 5–7 days (66%). The HCPs considerations while choosing BL-BLIs were mainly based on anti-microbial spectrum (81%), and rationality of BL/BLI combination (63%) and clinical experience with the BL-BLI molecule (63%). Cefoperazone-Sulbactam (CS) and Piperacillin–tazobactam (PT) were most commonly prescribed BL-BLIs and HCPs preferred the latter for pneumonia (67%), skin and soft-tissue infections (57%), bloodstream infections (67%) and cancer-associated febrile neutropenia (64%); while they preferred former for urinary tract infections (64%). CS and PT were preferred for intra-abdominal infections (57% and 64% respectively) and post-surgical infections (56% and 53% respectively). Conclusion CS and PT were the most commonly prescribed BL-BLIs probably due to their wide antimicrobial spectrum, rationality of the BL/BLI combination and the clinical experience with the molecules. BL-BLIs are still a mainstay of treatment for infections due to ESBL producing organisms. Disclosures All authors: No reported disclosures.
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Borgianni, Luisa, Julie Vandenameele, André Matagne, Luca Bini, Robert A. Bonomo, Jean-Marie Frère, Gian Maria Rossolini i Jean-Denis Docquier. "Mutational Analysis of VIM-2 Reveals an Essential Determinant for Metallo-β-Lactamase Stability and Folding". Antimicrobial Agents and Chemotherapy 54, nr 8 (24.05.2010): 3197–204. http://dx.doi.org/10.1128/aac.01336-09.
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ABSTRACT Metallo-β-lactamase (MBL)-producing bacteria are emerging worldwide and represent a formidable threat to the efficacy of relevant β-lactams, including carbapenems, expanded-spectrum cephalosporins, and β-lactamase inactivator/β-lactam combinations. VIM-2 is currently the most widespread MBL and represents a primary target for MBL inhibitor research, the clinical need for which is expected to further increase in the future. Using a saturation mutagenesis approach, we probed the importance of four residues (Phe-61, Ala-64, Tyr-67, and Trp-87) located close to the VIM-2 active site and putatively relevant to the enzyme activity based on structural knowledge of the enzyme and on structure-activity relationships of the subclass B1 MBLs. The ampicillin MIC values shown by the various mutants were affected very differently depending on the randomized amino acid position. Position 64 appeared to be rather tolerant to substitution, and kinetic studies showed that the A64W mutation did not significantly affect substrate hydrolysis or binding, representing an important difference from IMP-type enzymes. Phe-61 and Tyr-67 could be replaced with several amino acids without the ampicillin MIC being significantly affected, but in contrast, Trp-87 was found to be critical for ampicillin resistance. Further kinetic and biochemical analyses of W87A and W87F variants showed that this residue is apparently important for the structure and proper folding of the enzyme but, surprisingly, not for its catalytic activity. These data support the critical role of residue 87 in the stability and folding of VIM-2 and might have strong implications for MBL inhibitor design, as this residue would represent an ideal target for interaction with small molecules.
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Diarra, M. S., M. C. Lavoie, M. Jacques, I. Darwish, E. K. Dolence, J. A. Dolence, A. Ghosh, M. Ghosh, M. J. Miller i F. Malouin. "Species selectivity of new siderophore-drug conjugates that use specific iron uptake for entry into bacteria." Antimicrobial Agents and Chemotherapy 40, nr 11 (listopad 1996): 2610–17. http://dx.doi.org/10.1128/aac.40.11.2610.
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Siderophores selectively bind ferric iron and are involved in receptor-specific iron transport into bacteria. Several types of siderophores were synthesized, and growth-promoting or inhibitory activities when they were conjugated to carbacephalosporin, erythromycylamine, or nalidixic acid were investigated. Overall, 11 types of siderophores and 21 drug conjugates were tested against seven different bacterial species: Escherichia coli, Bordetella bronchiseptica, Pasteurella multocida, Pasteurella haemolytica, Streptococcus suis, Staphylococcus aureus, and Staphylococcus epidermidis. In some species, the inhibitory activities of the drug conjugates were associated with the ability of the bacteria to use the siderophore portion of the molecules for growth promotion in disc diffusion tests (0.04 mumol of conjugate or siderophore per disc). E. coli used catechol-based siderophore portions as well as hydroxamate-based tri-delta-OH-N-OH-delta-N-acetyl-L-ornithine ferric iron ligands for growth under iron-restricted conditions achieved by supplemental ethylenediamine di (O-hydroxyphenylacetic acid) (100 micrograms/ml) and was sensitive to carbacephalosporin conjugated to these siderophore types (up to a 34-mm-diameter inhibition zone). B. bronchiseptica used desferrioxamine B and an isocyanurate-based or trihydroxamate in addition to catechol-based siderophore portions for promotion but was not inhibited by beta-lactam conjugates partly because of the presence of beta-lactamase. P. multocida and P. haemolytica did not use any of the synthetic siderophores for growth promotion, and the inhibitory activities of some conjugates seemed partly linked to their ability to withhold iron from these bacteria, since individual siderophore portions showed some antibacterial effects. Individual siderophores did not promote S. suis growth in restrictive conditions, but the type of ferric iron ligands attached to beta-lactams affected inhibitory activities. The antibacterial activities of the intracellular-acting agents erythromycylamine and nalidixic acid were reduced or lost, even against S. aureus and S. epidermidis, when the agents were conjugated to siderophores. Conjugate-resistant E. coli mutants showed the absence of some iron-regulated outer membrane proteins in gel electrophoresis profiles and in specific phage or colicin sensitivity tests, implying that the drugs used outer membrane receptors of ferric complexes to get into cells.
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Bhagwanth, Swapna, Ram K. Mishra i Rodney L. Johnson. "Development of peptidomimetic ligands of Pro-Leu-Gly-NH2 as allosteric modulators of the dopamine D2 receptor". Beilstein Journal of Organic Chemistry 9 (30.01.2013): 204–14. http://dx.doi.org/10.3762/bjoc.9.24.
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A variety of stable, small-molecule peptidomimetic ligands have been developed to elucidate the mechanism by which the neuropeptide Pro-Leu-Gly-NH2 (PLG) modulates dopaminergic neurotransmission. Photoaffinity labeling ligands based upon PLG peptidomimetics have been used to establish that PLG binds to the D2 dopamine receptor at a site that is different from the orthosteric site, thus making PLG and its peptidomimetics allosteric modulators of the dopamine receptor. Through the design, synthesis and pharmacological evaluation of conformationally constrained peptidomimetics containing lactam, bicyclic, and spiro-bicyclic scaffolds, support was provided for the hypothesis that the bioactive conformation of PLG is a type II β-turn. In addition, studies with peptidomimetics designed to mimic either a type VI β-turn or polyproline II helix conformation yielded molecules that were able to modulate dopamine receptors because of their ability to place the carboxamide NH2 pharmacophore in the same topological space as that seen in the type II β-turn. Extensive studies with the spiro-bicyclic PLG peptidomimetics also established that both positive and negative modes of modulation were possible for the same series of peptidomimetics simply as a result of minor differences in the stereochemistry about the bridgehead carbon within the scaffold. This information was used to transform existing positive modulators into negative modulators, which demonstrated that small structural changes in the spiro-bicyclic dopamine receptor modulators are capable of causing major changes in the modulatory activity of PLG peptidomimetics.
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Biswal, Sarmistha, Karina Caetano, Diamond Jain, Anusha Sarrila, Tulika Munshi, Rachael Dickman, Alethea B. Tabor, Surya Narayan Rath, Sanjib Bhakta i Anindya S. Ghosh. "Antimicrobial Peptides Designed against the Ω-Loop of Class A β-Lactamases to Potentiate the Efficacy of β-Lactam Antibiotics". Antibiotics 12, nr 3 (10.03.2023): 553. http://dx.doi.org/10.3390/antibiotics12030553.
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Class A serine β-lactamases (SBLs) have a conserved non-active site structural domain called the omega loop (Ω-loop), in which a glutamic acid residue is believed to be directly involved in the hydrolysis of β-lactam antibiotics by providing a water molecule during catalysis. We aimed to design and characterise potential pentapeptides to mask the function of the Ω-loop of β-lactamases and reduce their efficacy, along with potentiating the β-lactam antibiotics and eventually decreasing β-lactam resistance. Considering the Ω-loop sequence as a template, a group of pentapeptide models were designed, validated through docking, and synthesised using solid-phase peptide synthesis (SPPS). To check whether the β-lactamases (BLAs) were inhibited, we expressed specific BLAs (TEM-1 and SHV-14) and evaluated the trans-expression through a broth dilution method and an agar dilution method (HT-SPOTi). To further support our claim, we conducted a kinetic analysis of BLAs with the peptides and employed molecular dynamics (MD) simulations of peptides. The individual presence of six histidine-based peptides (TSHLH, ETHIH, ESRLH, ESHIH, ESRIH, and TYHLH) reduced β-lactam resistance in the strains harbouring BLAs. Subsequently, we found that the combinational effect of these peptides and β-lactams sensitised the bacteria towards the β-lactam drugs. We hypothesize that the antimicrobial peptides obtained might be considered among the novel inhibitors that can be used specifically against the Ω-loop of the β-lactamases.
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Sharan, Deepti, i Erin E. Carlson. "Expanded profiling of β-lactam selectivity for penicillin-binding proteins in Streptococcus pneumoniae D39". Biological Chemistry 403, nr 4 (28.02.2022): 433–43. http://dx.doi.org/10.1515/hsz-2021-0386.
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Abstract Penicillin-binding proteins (PBPs) are integral to bacterial cell division as they mediate the final steps of cell wall maturation. Selective fluorescent probes are useful for understanding the role of individual PBPs, including their localization and activity during growth and division of bacteria. For the development of new selective probes for PBP imaging, several β-lactam antibiotics were screened, as they are known to covalently bind PBP in vivo. The PBP inhibition profiles of 16 commercially available β-lactam antibiotics were evaluated in an unencapsulated derivative of the D39 strain of Streptococcus pneumoniae, IU1945. These β-lactams have not previously been characterized for their PBP inhibition profiles in S. pneumoniae and these data augment those obtained from a library of 20 compounds that we previously reported. We investigated seven penicillins, three carbapenems, and six cephalosporins. Most of these β-lactams were found to be co-selective for PBP2x and PBP3, as was noted in our previous studies. Six out of 16 antibiotics were selective for PBP3 and one molecule was co-selective for PBP1a and PBP3. Overall, this work expands the chemical space available for development of future β-lactam-based probes for specific pneumococcal PBP labeling and these methods can be used for the development of probes for PBP labelling in other bacterial species.
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Anant, Prem Singh, i Pratima Gupta. "Application of machine learning in understanding bioactivity of beta-lactamase AmpC". Journal of Physics: Conference Series 2273, nr 1 (1.05.2022): 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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Aslanli, Aysel, i Elena Efremenko. "Simultaneous molecular docking of different ligands to His6-tagged organophosphorus hydrolase as an effective tool for assessing their effect on the enzyme". PeerJ 7 (12.09.2019): e7684. http://dx.doi.org/10.7717/peerj.7684.
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Background Enzymatic hydrolysis of N-acyl homoserine lactones (AHLs), which are signaling molecules responsible for the development of antibiotic resistance in gram-negative bacteria, is a potential solution to overcoming antibiotic resistance problem. It has been established that hexahistidine-tagged organophosphorus hydrolase (His6-OPH) exhibits lactonase activity against a number of AHLs and that the combined application of His6-OPH with β-lactam antibiotics leads to an increase in the efficiency of the action of both the enzyme and antibiotics. The use of computational methods can be an effective way to search for and select from the known antibiotics to find the most rational “partners” for combining with this enzyme and creating effective antibacterial agents with a dual (lactonase and antibacterial) functional activity. Methods In this study, by using AutoDock Vina and Gromacs softwares the molecular docking and the molecular dynamics methods were adopted to simulate models of puromycin, ceftiofur, and/or AHLs docked to the surface of a dimer molecule of His6-OPH and to study their binding properties. GABEDIT and GAMESS-US packages were used to generate and simulate electron densities of docked AHLs. Results Interactions of N-butyryl-DL-homoserine lactone (C4-HSL), N-(3-oxooctanoyl)-L-homoserine lactone (C8-HSL) and N-(3-oxododecanoyl)-L-homoserine lactone (C12-HSL) with His6-OPH dimer active sites in the presence of puromycin and ceftiofur were simulated and studied. The possible intersection of long-chain AHLs with antibiotic molecules in the active sites of the enzyme was revealed. The binding energies of antibiotics and AHLs with the His6-OPH surface were estimated. Statistically significant differences (p = 0.003) were observed between the values calculated for both C4-HSL and C12-HSL, whereas there were no statistically significant differences between the values of the other groups (p ≥ 0.100). The binding energies of AHLs with His6-OPH were slightly higher as compared with the binding energies of antibiotics with the enzyme. The dynamics of the most probable models obtained from docking were investigated. RMSD and RMSF analysis of His6-OPH-AHL complexes in the absence and presence of antibiotics were performed. The interaction energy values of antibiotics and AHLs with the His6-OPH were assessed. Significant increase of the AHLs steadiness in enzyme-substrate complexes in the presence of antibiotics was revealed. The interaction between His6-OPH and C12-HSL was established as thermodynamically more favored. Conclusions It has been established that the studied antibiotics puromycin and ceftiofur steady the enzyme-substrate complexes, but at the same time lead to a decrease in the long-chain AHL-hydrolytic activity of His6-OPH in such a combination as compared to a native enzyme, and, therefore, it should be taken into account when creating a therapeutic composition based on combining antibiotics with His6-OPH.
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Yamada, Masanori, i Itaru Honma. "An Anhydrous Proton Conductor Based on Lactam–Lactim Tautomerism of Uracil". ChemPhysChem 5, nr 5 (17.05.2004): 724–28. http://dx.doi.org/10.1002/cphc.200301015.
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Flores, Anthony R., Linda M. Parsons i Martin S. Pavelka. "Characterization of Novel Mycobacterium tuberculosis and Mycobacterium smegmatis Mutants Hypersusceptible to β-Lactam Antibiotics". Journal of Bacteriology 187, nr 6 (15.03.2005): 1892–900. http://dx.doi.org/10.1128/jb.187.6.1892-1900.2005.
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ABSTRACT Our laboratory previously constructed mutants of Mycobacterium tuberculosis and Mycobacterium smegmatis with deletions in the genes for their major β-lactamases, BlaC and BlaS, respectively, and showed that the mutants have increased susceptibilities to most β-lactam antibiotics, particularly the penicillins. However, there is still a basal level of resistance in the mutants to certain penicillins, and the susceptibilities of the mutants to some cephalosporin-based β-lactams are essentially the same as those of the wild types. We hypothesized that characterizing additional mutants (derived from β-lactamase deletion mutants) that are hypersusceptible to β-lactam antibiotics might reveal novel genes involved with other mechanisms of β-lactam resistance, peptidoglycan assembly, and cell envelope physiology. We report here the isolation and characterization of nine β-lactam antibiotic-hypersusceptible transposon mutants, two of which have insertions in genes known to be involved with peptidoglycan biosynthesis (ponA2 and dapB); the other seven mutants have insertions which affect novel genes. These genes can be classified into three groups: those involved with peptidoglycan biosynthesis, cell division, and other cell envelope processes. Two of the peptidoglycan-biosynthetic genes (ponA2 and pbpX) may encode β-lactam antibiotic-resistant enzymes proposed to be involved with the synthesis of the unusual diaminopimelyl linkages within the mycobacterial peptidoglycan.
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Bobba, Sudheer, V. K. Chaithanya Ponnaluri, Mridul Mukherji i William G. Gutheil. "Microtiter Plate-Based Assay for Inhibitors of Penicillin-Binding Protein 2a from Methicillin-Resistant Staphylococcus aureus". Antimicrobial Agents and Chemotherapy 55, nr 6 (14.03.2011): 2783–87. http://dx.doi.org/10.1128/aac.01327-10.
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ABSTRACTPenicillin-binding protein 2a (PBP2a), the molecular determinant for high-level β-lactam resistance in methicillin-resistantStaphylococcus aureus(MRSA), is intrinsically resistant to most β-lactam antibiotics. The development and characterization of new inhibitors targeting PBP2a would benefit from an effective and convenient assay for inhibitor binding. This study was directed toward the development of a fluorescently detected β-lactam binding assay for PBP2a from MRSA. Biotinylated ampicillin and biotinylated cephalexin were tested as tagging reagents for fluorescence detection by using a streptavidin-horseradish peroxidase conjugate. Both bound surprisingly well to PBP2a, with binding constants of 1.6 ± 0.4 μM and 13.6 ± 0.8 μM, respectively. Two forms of the assay were developed, a one-step direct competition form of the assay and a two-step indirect competition form of the assay, and both forms of the assay gave comparable results. This assay was then used to characterize PBP2a binding to ceftobiprole, which gave results consistent with previous studies of ceftobiprole-PBP2a binding. This assay was also demonstrated for screening for PBP2a inhibitors by screening a set of 13 randomly selected β-lactams for PBP2a inhibition at 750 μM. Meropenem was observed to give substantial inhibition in this screen, and a follow-up titration experiment determined its apparentKito be 480 ± 70 μM. The availability of convenient and sensitive microtiter-plate based assays for the screening and characterization of PBP2a inhibitors is expected to facilitate the discovery and development of new PBP2a inhibitors for use in combating the serious public health problem posed by MRSA.
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Listro, Roberta, Giacomo Rossino, Serena Della Volpe, Rita Stabile, Massimo Boiocchi, Lorenzo Malavasi, Daniela Rossi i Simona Collina. "Enantiomeric Resolution and Absolute Configuration of a Chiral δ-Lactam, Useful Intermediate for the Synthesis of Bioactive Compounds". Molecules 25, nr 24 (19.12.2020): 6023. http://dx.doi.org/10.3390/molecules25246023.
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During the past several years, the frequency of discovery of new molecular entities based on γ- or δ-lactam scaffolds has increased continuously. Most of them are characterized by the presence of at least one chiral center. Herein, we present the preparation, isolation and the absolute configuration assignment of enantiomeric 2-(4-bromophenyl)-1-isobutyl-6-oxopiperidin-3-carboxylic acid (trans-1). For the preparation of racemic trans-1, the Castagnoli-Cushman reaction was employed. (Semi)-preparative enantioselective HPLC allowed to obtain enantiomerically pure trans-1 whose absolute configuration was assigned by X-ray diffractometry. Compound (+)-(2R,3R)-1 represents a reference compound for the configurational study of structurally related lactams.
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del Corte, Xabier, Adrián López-Francés, Ilia Villate-Beitia, Myriam Sainz-Ramos, Edorta Martínez de Marigorta, Francisco Palacios, Concepción Alonso, Jesús M. de los Santos, José Luis Pedraz i Javier Vicario. "Multicomponent Synthesis of Unsaturated γ-Lactam Derivatives. Applications as Antiproliferative Agents through the Bioisosterism Approach: Carbonyl vs. Phosphoryl Group". Pharmaceuticals 15, nr 5 (22.04.2022): 511. http://dx.doi.org/10.3390/ph15050511.
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We report efficient synthetic methodologies for the preparation of 3-amino and 3-hydroxy 3-pyrrolin-2-ones (unsaturated γ-lactams) through a multicomponent reaction of amines, aldehydes and acetylene or pyruvate derivatives. The densely substituted γ-lactam substrates show in vitro cytotoxicity, inhibiting the growth of the carcinoma human tumor cell lines RKO (human colon epithelial carcinoma), SKOV3 (human ovarian carcinoma) and A549 (carcinomic human alveolar basal epithelial cell). In view of the possibilities for the diversity of the substituents that offer a multicomponent, synthetic methodology, an extensive structure–activity profile is presented. In addition, the bioisosteric replacement of the flat ester group by a tetrahedral phosphonate or phosphine oxide moiety in γ-lactam substrates leads to increased growth inhibition activity. Cell morphology analysis and flow cytometry assays indicate that the main pathway by which our compounds induce cytotoxicity is based on the activation of the intracellular apoptotic mechanism.
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Pathompong, Paomephan, Sebastian Pfütze, Frank Surup, Thitiya Boonpratuang, Rattaket Choeyklin, Josphat C. Matasyoh, Cony Decock, Marc Stadler i Chuenchit Boonchird. "Drimane-Type Sesquiterpenoids Derived from the Tropical Basidiomycetes Perenniporia centrali-africana and Cerrena sp. nov". Molecules 27, nr 18 (14.09.2022): 5968. http://dx.doi.org/10.3390/molecules27185968.
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Five new drimane-type sesquiterpenoids were isolated from cultures of the tropical basidiomycetes, Perenniporia centrali-africana (originating from Kenya) and Cerrena sp. nov. (originating from Thailand). A new pereniporin A derivative (1), a new drimane-type sesquiterpene lactam (2), and the new 6,7-Dehydro-isodrimenediol (3) were isolated from P. centrali-africana. In parallel, the two new drimane-type sesquiterpene lactams 5 and 6 were isolated together with known isodrimenediol (4) from Cerrena sp. This is the first report of drimane-type sesquiterpene lactams from basidiomycetes. The structures were elucidated based on 1D and 2D nuclear magnetic resonance (NMR) spectroscopic data, in combination with high-resolution electrospray mass spectrometric (HR-ESIMS) data. The compounds were devoid of significant antimicrobial and cytotoxic activities.
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Collia, Deanna, Thomas D. Bannister, Hao Tan, Shouguang Jin, Taimour Langaee, Justin Shumate, Louis Scampavia i Timothy P. Spicer. "A Rapid Phenotypic Whole-Cell Screening Approach for the Identification of Small-Molecule Inhibitors That Counter β-Lactamase Resistance in Pseudomonas aeruginosa". SLAS DISCOVERY: Advancing the Science of Drug Discovery 23, nr 1 (29.08.2017): 55–64. http://dx.doi.org/10.1177/2472555217728489.
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Pseudomonas aeruginosa is an opportunistic human pathogen that is prevalent in hospitals and continues to develop resistance to multiple classes of antibiotics. Historically, β-lactam antibiotics have been the first line of therapeutic defense. However, the emergence of multidrug-resistant (MDR) strains of P. aeruginosa, such as AmpC β-lactamase overproducing mutants, limits the effectiveness of current antibiotics. Among AmpC hyperproducing clinical isolates, inactivation of AmpG, which is essential for the expression of AmpC, increases bacterial sensitivity to β-lactam antibiotics. We hypothesize that inhibition of AmpG activity will enhance the efficacy of β-lactams against P. aeruginosa. Here, using a highly drug-resistant AmpC-inducible laboratory strain PAO1, we describe an ultra-high-throughput whole-cell turbidity assay designed to identify small-molecule inhibitors of the AmpG. We screened 645,000 compounds to identify compounds with the ability to inhibit bacterial growth in the presence of cefoxitin, an AmpC inducer, and identified 2663 inhibitors that were also tested in the absence of cefoxitin to determine AmpG specificity. The Z′ and signal-to-background ratio were robust at 0.87 ± 0.05 and 2.2 ± 0.2, respectively. Through a series of secondary and tertiary studies, including a novel luciferase-based counterscreen, we ultimately identified eight potential AmpG-specific inhibitors.
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Liu, Xinyu, Shengjie Dong, Yuru Ma, Hu Xu, Hongxia Zhao i Qingzhi Gao. "N-(Sulfamoylbenzoyl)-L-proline Derivatives as Potential Non-β-lactam ESBL Inhibitors: Structure-Based Lead Identification, Medicinal Chemistry and Synergistic Antibacterial Activities". Medicinal Chemistry 15, nr 2 (12.02.2019): 196–206. http://dx.doi.org/10.2174/1573406414666180816123232.
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Background: There is an urgent need to develop novel inhibitors against clinically widespread extended-spectrum β-lactamases (ESBLs) to meet the challenges of the ever-evolving threat of antibiotic resistances. Most existing ESBL inhibitors sharing a common chemical feature of β-lactam ring in their molecule, this structural characteristic makes them intrinsically susceptible to enzymatic breakdown by the resistance mechanisms employed by the bacteria. Objective: The aim of this study was to screen and discover novel lead compounds by using Lproline as initial scaffold to create a “non-sulfur, non-β-lactam” new chemotypes for potential ESBL inhibitors. Methods: Structure-based molecular docking and virtual screening were employed in the novel inhibitor generation process for lead compound screening and SAR analysis. Evaluation of the ESBL inhibitory activity of the lead compounds was performed in combination with three of the most susceptible antibiotics: ceftazidime, meropenem and ampicillin, against thirteen ESBL enzymes including four new CTX-M harboring strains and four KPC-2 producing species. Results: L-proline derived (S)-1-(2-sulfamoylbenzoyl)pyrrolidine-2-carboxylic acid (compound 6) as a “non-sulfur, non-β-lactam” and the most potential ESBL inhibitor was identified. Compound 6 possesses ideal anti-resistance activities by reducing MICs of ceftazidime, meropenem and ampicillin by 16-133, 32-133 and 67-267 fold respectiveily. The inhibitory mechanism of 6 with CTX-M, KPC-2 and penicillinase were proposed and probed with molecular docking analysis. Conclusion: Given that the simple proline derivative but promising synergistic antibacterial properties of compound 6 augers well for further investigations into its in vivo efficacy.
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Ahmadvand, Parvaneh, Johannetsy J. Avillan, Jacob A. Lewis, Douglas R. Call i ChulHee Kang. "Characterization of Interactions between CTX-M-15 and Clavulanic Acid, Desfuroylceftiofur, Ceftiofur, Ampicillin, and Nitrocefin". International Journal of Molecular Sciences 23, nr 9 (7.05.2022): 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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Abordo, Alecks Megxel S., Mark B. Carascal, Roland Remenyi, Doralyn S. Dalisay i Jonel P. Saludes. "Clinically Isolated β-Lactam-Resistant Gram-Negative Bacilli in a Philippine Tertiary Care Hospital Harbor Multi-Class β-Lactamase Genes". Pathogens 12, nr 8 (8.08.2023): 1019. http://dx.doi.org/10.3390/pathogens12081019.
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In the Philippines, data are scarce on the co-occurrence of multiple β-lactamases (BLs) in clinically isolated Gram-negative bacilli. To investigate this phenomenon, we characterized BLs from various β-lactam-resistant Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa isolated from a Philippine tertiary care hospital. The selected Gram-negative bacilli (n = 29) were resistant to either third-generation cephalosporins (resistance category 1 (RC1)), cephalosporins and penicillin-β-lactamase inhibitors (RC2), or carbapenems (RC3). Isolates resistant to other classes of antibiotics but susceptible to early-generation β-lactams were also selected (RC4). All isolates underwent antibiotic susceptibility testing, disk-diffusion-based BL detection assays, and PCR with sequence analysis of extended-spectrum BLs (ESBLs), metallo-BLs, AmpC BLs, and oxacillinases. Among the study isolates, 26/29 harbored multi-class BLs. All RC1 isolates produced ESBLs, with blaCTX-M as the dominant (19/29) gene. RC2 isolates produced ESBLs, four of which harbored blaTEM plus blaOXA-1 or other ESBL genes. RC3 isolates carried blaNDM and blaIMP, particularly in three of the metallo-BL producers. RC4 Enterobacteriaceae carried blaCTX-M, blaTEM, and blaOXA-24-like, while A. baumannii and P. aeruginosa in this category carried either blaIMP or blaOXA-24. Genotypic profiling, in complement with phenotypic characterization, revealed multi-class BLs and cryptic metallo-BLs among β-lactam-resistant Gram-negative bacilli.
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T. Mohd Ali, M., i . "Synthesis of -Hydroxy -Proline: Potential for Organocataly-sis Reactions". International Journal of Engineering & Technology 7, nr 4.14 (24.12.2019): 237. http://dx.doi.org/10.14419/ijet.v7i4.14.27571.
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A chiral organic molecule, L-proline catalyzed an enantioselective transformation reaction has becoming interesting synthetic protocol especially in the area of organocatalysis. Herein, a synthetic approach towards -hydroxy--proline starting from bicyclic lactone lactam is hereby described. The syntheses utilized dicarboxylation reaction of bicyclic lacton lactam, followed by ether hydrolysis of the bicyclic ether and oxidation reaction of the primary alcohol. The synthetic strategy disclosed here allows further the enantioselective synthesis of a variety of unnatural amino acids based on -proline structure.
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Franceschini, Nicola, Berardo Caravelli, Jean-Denis Docquier, Moreno Galleni, Jean-Marie Frère, Gianfranco Amicosante i Gian Maria Rossolini. "Purification and Biochemical Characterization of the VIM-1 Metallo-β-Lactamase". Antimicrobial Agents and Chemotherapy 44, nr 11 (1.11.2000): 3003–7. http://dx.doi.org/10.1128/aac.44.11.3003-3007.2000.
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ABSTRACT VIM-1 is a new group 3 metallo-β-lactamase recently detected in carbapenem-resistant nosocomial isolates of Pseudomonas aeruginosa from the Mediterranean area. In this work, VIM-1 was purified from an Escherichia coli strain carrying the cloned bla VIM-1 gene by means of an anion-exchange chromatography step followed by a gel permeation chromatography step. The purified enzyme exhibited a molecular mass of 26 kDa in sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and an acidic pI of 5.1 in analytical isoelectric focusing. Amino-terminal sequencing showed that mature VIM-1 results from the removal of a 26-amino-acid signal peptide from the precursor. VIM-1 hydrolyzes a broad array of β-lactam compounds, including penicillins, narrow- to expanded-spectrum cephalosporins, carbapenems, and mechanism-based serine-β-lactamase inactivators. Only monobactams escape hydrolysis. The highest catalytic constant/Km ratios (>106M−1 · s−1) were observed with carbenicillin, azlocillin, some cephalosporins (cephaloridine, cephalothin, cefuroxime, cefepime, and cefpirome), imipenem, and biapenem. Kinetic parameters showed remarkable variability with different β-lactams and also within the various penam, cephem, and carbapenem compounds, resulting in no clear preference of the enzyme for any of these β-lactam subfamilies. Significant differences were observed with some substrates between the kinetic parameters of VIM-1 and those of other metallo-β-lactamases. Inactivation assays carried out with various chelating agents (EDTA, 1,10-o-phenanthroline, and pyridine-2,6-dicarboxylic acid) indicated that formation of a ternary enzyme-metal-chelator complex precedes metal removal from the zinc center of the protein and revealed notable differences in the inactivation parameters of VIM-1 with different agents.
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Górecki, Marcin, i Jadwiga Frelek. "A Holistic Approach to Determining Stereochemistry of Potential Pharmaceuticals by Circular Dichroism with β-Lactams as Test Cases". International Journal of Molecular Sciences 23, nr 1 (27.12.2021): 273. http://dx.doi.org/10.3390/ijms23010273.
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This paper’s main objective is to show that many different factors must be considered when solving stereochemical problems to avoid misleading conclusions and obtain conclusive results from the analysis of spectroscopic properties. Particularly in determining the absolute configuration, the use of chiroptical methods is crucial, especially when other techniques, including X-ray crystallography, fail, are not applicable, or give inconclusive results. Based on various β-lactam derivatives as models, we show how to reliably determine their absolute configuration (AC) and preferred conformation from circular dichroism (CD) spectra. Comprehensive CD analysis, employing both approaches, i.e., traditional with their sector and helicity rules, and state-of-the-art supported by quantum chemistry (QC) calculations along with solvation models for both electronic (ECD) and vibrational (VCD) circular dichroism ranges, allows confident defining stereochemistry of the β-lactams studied. Based on an in-depth analysis of the results, we have shown that choosing a proper chiroptical method/s strictly depends on the specific case and certain structural features.
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Konaklieva, Monika. "Molecular Targets of β-Lactam-Based Antimicrobials: Beyond the Usual Suspects". Antibiotics 3, nr 2 (3.04.2014): 128–42. http://dx.doi.org/10.3390/antibiotics3020128.
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Piotrowska, Marta, Lukasz Dziewit, Rafał Ostrowski, Cora Chmielowska i Magdalena Popowska. "Molecular Characterization and Comparative Genomics of IncQ-3 Plasmids Conferring Resistance to Various Antibiotics Isolated from a Wastewater Treatment Plant in Warsaw (Poland)". Antibiotics 9, nr 9 (17.09.2020): 613. http://dx.doi.org/10.3390/antibiotics9090613.
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As small, mobilizable replicons with a broad host range, IncQ plasmids are widely distributed among clinical and environmental bacteria. They carry antibiotic resistance genes, and it has been shown that they confer resistance to β-lactams, fluoroquinolones, aminoglycosides, trimethoprim, sulphonamides, and tetracycline. The previously proposed classification system divides the plasmid group into four subgroups, i.e., IncQ-1, IncQ-2, IncQ-3, and IncQ-4. The last two subgroups have been poorly described so far. The aim of this study was to analyze five newly identified IncQ-3 plasmids isolated from a wastewater treatment plant in Poland and to compare them with all known plasmids belonging to the IncQ-3 subgroup whose sequences were retrieved from the NCBI database. The complete nucleotide sequences of the novel plasmids were annotated and bioinformatic analyses were performed, including identification of core genes and auxiliary genetic load. Furthermore, functional experiments testing plasmid mobility were carried out. Phylogenetic analysis based on three core genes (repA, mobA/repB, and mobC) revealed the presence of three main clusters of IncQ-3 replicons. Apart from having a highly conserved core, the analyzed IncQ-3 plasmids were vectors of antibiotic resistance genes, including (I) the qnrS2 gene that encodes fluoroquinolone resistance and (II) β-lactam, trimethoprim, and aminoglycoside resistance genes within integron cassettes.
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Vitus Silago. "Beta-lactam antibiotics and extended spectrum beta-lactamases". GSC Advanced Research and Reviews 9, nr 2 (30.11.2021): 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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Wolfe, Saul, i Tova Hoz. "A semiempirical molecular orbital study of the methanolysis of complex azetidinones. A combined MM and QM analysis of the interaction of Δ2- and Δ3-cephems with the penicillin receptor". Canadian Journal of Chemistry 72, nr 4 (1.04.1994): 1044–50. http://dx.doi.org/10.1139/v94-132.
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The semiempirical molecular orbital procedures MINDO/3, MNDO, MNDO/M, AM1, and PM3 have been used to examine possible mechanisms and modes of attack of methanol on penam, the bicyclic ring system of penicillin. These mechanisms include a one-step process in which C—O bond formation from the convex face of the molecule and proton transfer to the β-lactam nitrogen are concerted with the cleavage of the N—C(O) bond (the N-protonated pathway), and two O-protonated pathways, viz., addition to the β-lactam carbonyl group from the convex face and from the concave face of the bicyclic ring system. Only MINDO/3 reproduces the ab initio MP2/6-31G*//3-21G* trends, that the N-protonated pathway is energetically preferred over either O-protonated pathway, and, in the latter, attack from the convex face is slightly preferred over attack from the concave face. MINDO/3 has, therefore, been used for a systematic examination of the reactions of many substituted and unsubstituted β-lactam-containing ring systems with methanol. The N-protonated structure created by attack of the alcohol from the convex face of the molecule is always preferred, and structure–reactivity relationships are observed that parallel structure–activity relationships of β-lactam antibiotics. MINDO/3 has also been used to compute a scaled quantum mechanical force field for Δ2- and Δ3-cephems. This has allowed parameters to be proposed for Δ2- and Δ3-cephems in the force field of Allinger's MMP2(85) programme that complement earlier parameterizations of the program for penicillins and peptides. The availability of these parameters has led to the development of a protocol for the analysis of the differences in the antibacterial activities of penicillins and cephalosporins. The analysis is based on a combination of "fit" and "reactivity" at the site of action. Fit is determined from the geometry that results when the β-lactam compound is complexed to a hexapeptide model of the penicillin receptor, in particular, the four-centred interaction between C-O-H of the active site serine residue and (O)C-N of the azetidinone ring. Reactivity is derived from MINDO/3 calculations of ΔE≠ for the reaction of methanol with the different ring systems via the N-protonated pathway. Δ3-Cephalosporins are suggested to be inherently less active than penicillins because they are inherently less reactive. Δ2-Cephalosporins containing a 4α-oriented carboxyl group are much less active than Δ3-cephalosporins because they have a much poorer fit. The 4β epimers of these Δ2-cephalosporins are much less active than Δ3-cephalosporins because they are much less reactive.
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Louis, Bruno, i Vijay K. Agrawal. "Quantitative structure-pharmacokinetic relationship (QSPkP) analysis of the volume of distribution values of anti-infective agents from j group of the ATC classification in humans". Acta Pharmaceutica 62, nr 3 (1.09.2012): 305–23. http://dx.doi.org/10.2478/v10007-012-0024-z.
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In this study, a quantitative structure-pharmacokinetic relationship (QSPkR) model for the volume of distribution (Vd) values of 126 anti-infective drugs in humans was developed employing multiple linear regression (MLR), artificial neural network (ANN) and support vector regression (SVM) using theoretical molecular structural descriptors. A correlation-based feature selection (CFS) was employed to select the relevant descriptors for modeling. The model results show that the main factors governing Vd of anti-infective drugs are 3D molecular representations of atomic van der Waals volumes and Sanderson electronegativities, number of aliphatic and aromatic amino groups, number of beta-lactam rings and topological 2D shape of the molecule. Model predictivity was evaluated by external validation, using a variety of statistical tests and the SVM model demonstrated better performance compared to other models. The developed models can be used to predict the Vd values of anti-infective drugs.
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Elliott, Jason M., Emma J. Carlson, Gary G. Chicchi, Olivier Dirat, Maria Dominguez, Ute Gerhard, Richard Jelley i in. "NK1 antagonists based on seven membered lactam scaffolds". Bioorganic & Medicinal Chemistry Letters 16, nr 11 (czerwiec 2006): 2929–32. http://dx.doi.org/10.1016/j.bmcl.2006.02.080.
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Ali, Tanveer, Abdul Basit, Asad Mustafa Karim, Jung-Hun Lee, Jeong-Ho Jeon, Shafiq ur Rehman i Sang-Hee Lee. "Mutation-Based Antibiotic Resistance Mechanism in Methicillin-Resistant Staphylococcus aureus Clinical Isolates". Pharmaceuticals 14, nr 5 (1.05.2021): 420. http://dx.doi.org/10.3390/ph14050420.
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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.
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Sanbongi, Yumiko, Takahisa Suzuki, Yumi Osaki, Nami Senju, Takashi Ida i Kimiko Ubukata. "Molecular Evolution of β-Lactam-Resistant Haemophilus influenzae: 9-Year Surveillance of Penicillin-Binding Protein 3 Mutations in Isolates from Japan". Antimicrobial Agents and Chemotherapy 50, nr 7 (lipiec 2006): 2487–92. http://dx.doi.org/10.1128/aac.01316-05.
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ABSTRACT A total of 621 clinical isolates of Haemophilus influenzae collected in Japan between 1995 and 2003 were studied for their susceptibilities to several antimicrobial agents, β-lactamase production, and amino acid substitutions in penicillin-binding protein 3 (PBP 3). Over the four study periods (first period, 1995 to 1996; second period, 1997 to 1998; third period, 2000 to 2001; fourth period, 2002 to 2003), the susceptibilities to β-lactam agents decreased and the incidence of isolates with substitutions at positions 377, 385, 389, 517, and/or 526 in PBP 3 increased from 28.8% to 52.0%. Five hundred seventy-one β-lactamase-nonproducing isolates were grouped into 18 classes, based on the pattern of the five mutations in PBP 3. The Asp526Lys substitution led to 6.0-, 4.3-, 2.4-, and 5.4-fold increases in amoxicillin-clavulanic acid, cefdinir, cefditoren, and faropenem resistance, respectively. PBP 3 with multiple substitutions (Met377Ile, Ser385Thr, and/or Leu389Phe) together with Asp526Lys resulted in increased resistance compared to that for PBP 3 with the Asp526Lys substitution alone. These results indicate that mutations at these five positions increased resistance to most β-lactams. Although a significant change in the prevalence of β-lactamase-producing strains was not observed, the proportions of those possessing both PBP 3 alterations and β-lactamase production have slightly increased (from 1.4% to 5.0%). The ROB-1 β-lactamase was rare, but this is the first report of this β-lactamase in Japan.
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Biondi, S., S. Long, M. Panunzio i W. L. Qin. "Current Trends in β-Lactam Based β-Lactamases Inhibitors". Current Medicinal Chemistry 18, nr 27 (1.09.2011): 4223–36. http://dx.doi.org/10.2174/092986711797189655.
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