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The understanding of how central metabolism and fermentation pathways regulate antimicrobial susceptibility in the anaerobic pathogen Bacteroides fragilis is still incomplete. Our study reveals that B. fragilis encodes two iron-dependent, redox-sensitive regulatory pirin protein genes, pir1 and pir2. The mRNA expression of these genes increases when exposed to oxygen and during growth in iron-limiting conditions. These proteins, Pir1 and Pir2, influence the production of short-chain fatty acids and modify the susceptibility to metronidazole and amixicile, a new inhibitor of pyruvate: ferredoxin oxidoreductase in anaerobes. We have demonstrated that Pir1 and Pir2 interact directly with this oxidoreductase, as confirmed by two-hybrid system assays. Furthermore, structural analysis using AlphaFold2 predicts that Pir1 and Pir2 interact stably with several central metabolism enzymes, including the 2-ketoglutarate:ferredoxin oxidoreductases Kor1AB and Kor2CDAEBG. We used a series of metabolic mutants and electron transport chain inhibitors to demonstrate the extensive impact of bacterial metabolism on metronidazole and amixicile susceptibility. We also show that amixicile is an effective antimicrobial against B. fragilis in an experimental model of intra-abdominal infection. Our investigation led to the discovery that the kor2AEBG genes are essential for growth and have dual functions, including the formation of 2-ketoglutarate via the reverse TCA cycle. However, the metabolic activity that bypasses the function of Kor2AEBG following the addition of phospholipids or fatty acids remains undefined. Overall, our study provides new insights into the central metabolism of B. fragilis and its regulation by pirin proteins, which could be exploited for the development of new narrow-spectrum antimicrobials in the future.
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Antibacterianos , Bacteroides fragilis , Metronidazol , Bacteroides fragilis/genética , Bacteroides fragilis/efectos de los fármacos , Bacteroides fragilis/enzimología , Bacteroides fragilis/metabolismo , Metronidazol/farmacología , Metronidazol/metabolismo , Antibacterianos/farmacología , Antibacterianos/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Pruebas de Sensibilidad Microbiana , Regulación Bacteriana de la Expresión GénicaRESUMEN
The liveliness of a human potentially depends on his/her smooth movability. To accomplish the work of daily life, the joints of the body need to be healthy. However, the occurrence of Rheumatoid arthritis and Osteoarthritis has a significant prevalence towards the immovability of humankind. Rheumatoid arthritis (RA) and Osteoarthritis (OA) mostly affect the joints of the hand and knee which result in lifelong pain, inability to climb, walk, etc. In the early stages, these diseases attack the synovial membrane and synovial fluid, and further it destroys the soft tissues and bone structure. By early diagnosis, we can start the treatment in the early stage which may cure these diseases with such extreme consequences. As per clinical studies of previous literature, it is observed that synovial fluid imbalance appears in the early stage of such diseases and Hyaluronic Acid (HA) concentration also decreases for that. Therefore, estimation of HA is a significant key to arthritis disease classification and grading. In this paper, we proposed a hybrid framework for classification of arthritic knee joints based on the analysis of the discontinuous appearances of the HA concentration using infrared imaging technology. To meet up the specific necessities, firstly we have proposed a modified K-Means clustering algorithm for extraction of the region of interest (ROI) i.e., the knee joint surface. Secondly, a mathematical formulation is proposed to calculate the concentration of HA from the segmented ROIs. This experimental process was implemented on the publicly available IR (Infrared) Knee Joint Dataset and for further evaluation of the novelty of mathematical formulation, we have extended the proposed work to the classification of healthy and arthritis affected knee joints depending on significant discriminative characteristics of the HA concentration with respect to the existing significant imaging features. Experimental results and analysis demonstrates that concentration of HA has the dominant potential for classifying healthy and arthritic knee joints using infrared holistic images. Our experimental analysis reveals that estimation and combination of the HA concentration features with conventional handcrafted and deep features increases the classification performance with an average accuracy of 91% and 97.22% respectively as compared to the each individual feature sets.
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In today's medical research, breast cancer is a severe problem, so it is imperative to develop a reliable and efficient approach for identifying cancerous breast cells. PCF, with its exceptional sense-making abilities, simplifies and distinguishes that procedure. The research presents a unique structural hybrid PCF for detecting breast cancer cells using sensors based on PCF that are specifically built for the terahertz-frequency range. The improvement in sensor sensitivity and specificity in identifying cancer cells at these frequencies is a notable progress compared to conventional approaches, which could potentially result in earlier and more precise diagnosis. In our analysis, we discovered the most common malignancies in breast cancer. We investigate the features of the cancerous cell detector using the COMSOL-Multiphysics 5.6 software. This PCF detector achieves a Confinement Loss of 4.75 × 10-12 and 3.42 × 10-13 dB/m for Type-1 and Type-2 cancer cells, respectively, at 1.2 THz, as well as about 99.946% and 99.969% relative sensitivity. This sensor ensures the highest level of sensitivity for the identification of cancerous breast cells. This sensor's physical architecture is quite straightforward, making it simple to build using current manufacturing techniques. Therefore, it seems that this sensor will pave a new path for identifying and treating cancerous cells.
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Lactate elevation is a well-characterized biomarker of mitochondrial dysfunction, but its role in diabetic kidney disease (DKD) is not well defined. Urine lactate was measured in patients with type 2 diabetes (T2D) in 3 cohorts (HUNT3, SMART2D, CRIC). Urine and plasma lactate were measured during euglycemic and hyperglycemic clamps in participants with type 1 diabetes (T1D). Patients in the HUNT3 cohort with DKD had elevated urine lactate levels compared with age- and sex-matched controls. In patients in the SMART2D and CRIC cohorts, the third tertile of urine lactate/creatinine was associated with more rapid estimated glomerular filtration rate decline, relative to first tertile. Patients with T1D demonstrated a strong association between glucose and lactate in both plasma and urine. Glucose-stimulated lactate likely derives in part from proximal tubular cells, since lactate production was attenuated with sodium-glucose cotransporter-2 (SGLT2) inhibition in kidney sections and in SGLT2-deficient mice. Several glycolytic genes were elevated in human diabetic proximal tubules. Lactate levels above 2.5 mM potently inhibited mitochondrial oxidative phosphorylation in human proximal tubule (HK2) cells. We conclude that increased lactate production under diabetic conditions can contribute to mitochondrial dysfunction and become a feed-forward component to DKD pathogenesis.
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Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Glucólisis , Ácido Láctico , Humanos , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Animales , Ratones , Ácido Láctico/metabolismo , Ácido Láctico/sangre , Femenino , Masculino , Persona de Mediana Edad , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/complicaciones , Mitocondrias/metabolismo , Adulto , Tasa de Filtración Glomerular , Anciano , Túbulos Renales Proximales/metabolismo , Glucosa/metabolismo , Fosforilación Oxidativa , Biomarcadores/metabolismo , Transportador 2 de Sodio-Glucosa/metabolismo , Transportador 2 de Sodio-Glucosa/genética , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacologíaRESUMEN
The article divulges the crystal growth, synthesis, and X-ray structure characterization of one centrosymmetric cadmium complex, [Cd{CdL(µ2-1,3-acetate)}2] using Salen ligand (SL). The complex is further characterized using spectroscopic and analytical techniques, including DRS, SEM-EDX, PXRD, and ICP-MS. The crystallographic study showed that the complex has a monoclinic space P21/c. Addison parameters (Æ®) show the hexagonal geometry of the central Cd(II) metal ion. Hirshfeld surface and 2-D fingerprint confirm supramolecular contacts despite weak C-Hâ¯O and C-H···π interactions. Energy frameworks, FMOs, global reactivity parameters, MEP, and energy bandgap explain the complex reactivity outlook. The complex inter- and intramolecular bonding interactions were explored through natural bond orbital (NBO), QTAIM, NCI-RDG, Electron Location Function (ELF), and Localized Orbital Locator (LOL) quantization methods. In addition, the complex and its synthetic components in vitro antibacterial efficacy were investigated using Gram-positive and Gram-negative microbial strains. SAR (structure-activity relationship) correlates with biological potency. Molecular docking assessed antimicrobial potency with proteins S. aureus (PDB ID: 1JIJ), C. albicans (PDB ID: 1M7A), E. coli (PDB ID: 1T9U), P. aeruginosa (PDB ID: 2UV0), and A. Niger (PDB ID: 3K4P). The findings are backed by the Protein-Ligand Interaction Profiler (PLIP). The antifungal potency and cell viability test of C. albicans were conducted using photodynamic therapy (APDT).
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This work explores one centrosymmetric binuclear Cu(ii)-Salen complex synthesis, characterization, photosensitive Schottky barrier diode (PSBD) function, and DFT spectrum. The crystal growth involves H2LSAL and Cu(NO3)2·3H2O in CH3OH + ACN (acetonitrile) solvent medium. Herein, structural characterization employs elemental, IR/Raman, NMR, UV-VIS, DRS, SEM-EDX, PXRD, SCXRD, and XPS analyses. The complex crystal size is 0.2 × 0.2 × 0.2, showing monoclinic space group C2/c. The dimeric unit contains two Cu(ii) centres with distorted square pyramidal (SQP) geometries. The crystal packing consists of weak C-Hâ¯O interactions. DFT and Hirshfeld surface (HS) further substantiated the packing interactions, providing valuable insights into the underlying mechanisms. The 2-D fingerprint plots showed the presence of Nâ¯H (3%) and Oâ¯H (8.2%) contacts in the molecular arrangement. NBO, QTAIM, ELF-LOL, and energy frameworks are utilized to investigate the bonding features of the complex. We extensively studied electrical conductivity and PSBD for H2LSAL and the complex based on band gap (3.09 and 3.07 eV). Like an SBD, the complex has better electrical conductivity, evidencing potentiality in optoelectronic device applications. Optical response enhances conductivity, according to I-V characteristics. Complex Schottky diode has lower barrier height, resistance, and higher conductivity under light. The complex transports charge carriers through space and is rationalized by the 'hopping process' and 'structure-activity-relationship' (SAR). The charge transport mechanism was analysed by estimating complex mobility (µeff), lifetime (τ), and diffusion length (LD). The experimental and theoretical DOS/PDOS plots provide evidence for the Schottky diode function of the complex.
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Site-selective ortho/ipso C-H difunctionalizations of aromatic compounds were designed to afford polyfunctionalized arenes including challenging 1,2,3,4-tetrasubstituted ones (62â examples, up to 97 % yields). To ensure the excellent regioselectivity of the process while keeping high efficiency, an original strategy based on a "C-H thianthenation/Catellani-type reaction" sequence was developed starting from simple arenes. Non-prefunctionalized arenes were first regioselectively converted into the corresponding thianthrenium salts. Then, a palladium-catalyzed, norbornene (NBE)-mediated process allowed the synthesis of ipso-olefinated/ortho-alkylated polyfunctionalized arenes using a thianthrene as a leaving group (revisited Catellani reaction). Pleasingly, using a commercially available norbornene (NBE) and a unique catalytic system, synthetic challenges known for the Catellani reaction with aryl iodides were smoothly and successfully tackled with the "thianthrenium" approach. The protocol was robust (gram-scale reaction) and was widely applied to the two-fold functionalization of various arenes including bio-active compounds. Moreover, a panel of olefins and alkyl halides as coupling partners was suitable. Pleasingly, the "thianthrenium" strategy was successfully further applied to the incorporation of other groups at the ipso (CN/alkyl/H, aryl) and ortho (alkyl, aryl, amine, thiol) positions, showcasing the generality of the process.
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Reduced kidney AMPK activity is associated with nutrient stress-induced chronic kidney disease (CKD) in male mice. In contrast, female mice resist nutrient stress-induced CKD. The role of kidney AMPK in sex-related organ protection against nutrient stress and metabolite changes was evaluated in diabetic kidney tubule-specific AMPKγ2KO (KTAMPKγ2ΚΟ) male and female mice. In wild-type (WT) males, diabetes increased albuminuria, urinary kidney injury molecule-1, hypertension, kidney p70S6K phosphorylation, and kidney matrix accumulation; these features were not exacerbated with KTAMPKγ2ΚΟ. Whereas WT females had protection against diabetes-induced kidney injury, KTAMPKγ2ΚΟ led to loss of female protection against kidney disease. The hormone 17ß-estradiol ameliorated high glucose-induced AMPK inactivation, p70S6K phosphorylation, and matrix protein accumulation in kidney tubule cells. The mechanism for female protection against diabetes-induced kidney injury is likely via an estrogen-AMPK pathway, as inhibition of AMPK led to loss of estrogen protection to glucose-induced mTORC1 activation and matrix production. RNA sequencing and metabolomic analysis identified a decrease in the degradation pathway of phenylalanine and tyrosine resulting in increased urinary phenylalanine and tyrosine levels in females. The metabolite levels correlated with loss of female protection. The findings provide new insights to explain evolutionary advantages to females during states of nutrient challenges.
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Proteínas Quinasas Activadas por AMP , Nefropatías Diabéticas , Riñón , Animales , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/prevención & control , Femenino , Masculino , Ratones , Proteínas Quinasas Activadas por AMP/metabolismo , Riñón/metabolismo , Ratones Noqueados , Fosforilación , Estradiol/metabolismo , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Proteínas Quinasas S6 Ribosómicas 70-kDa/genética , Diabetes Mellitus Experimental/metabolismoRESUMEN
An efficient and interesting N-centered umpolung method has been disclosed to construct beneficial S-N bonds, furnishing N-sulfenylimines, which can readily be converted into the corresponding sulfonamide derivatives in a one-pot sequential operation. N-Sulfenylimines are potent intermediates in organic synthesis, whereas sulfonamides are of major molecular interest due to their rich biological activities and wide applicability in medicinal chemistry. Owing to the simple reaction conditions and setup, this protocol displays a broad and versatile substrate scope, resulting in excellent functional group tolerability toward the synthesis of both N-sulfenylimines and sulfonamides. A density functional theory (DFT) computed and experimentally supported convenient mechanism has been proposed for this unique method.
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In this work, one new centrosymmetric trinuclear Zn(II) complex 1, [{(OCN)Zn(L)}2Zn], using a salen-type ligand (H2L) in the presence of OCN- was synthesized and characterized via elemental, spectral, SEM-EDX, and single-crystal X-ray diffraction (SCXRD) study. In 1, SCXRD reveals two different stereochemical environments of zinc metal ions; one terminal Zn(II) center adopts square pyramidal geometries with the Addison parameter (τ) 0.095, and the central Zn(II) is tetracoordinated tetrahedral geometry. This article provides evidence of the significance and presence of spodium bonds (SpBs) in solid-state crystal structures involving a pseudotetrahedral environment of the central Zn-atom. X-ray structures reveal intramolecular Zn···O SpBs caused by the methoxy (-OCH3) substituent O-atom adjacent to the coordinated phenoxy O-atom. These noncovalent interactions have been thoroughly studied using density functional theory calculations at the RI-BP86[2]-D3[3]/def2-TZVP level of theory that characterizes the nature of SpBs, including the Baders quantum theory of atoms-in-molecules "QTAIM", molecular electrostatic potential (MEP) surface, and noncovalent index plot (NCI). In addition, a unique complex-isomer-based theoretical model has been vividly employed to estimate the SpBs energy in the complex. Natural bond orbital (NBO) analysis also tries to establish the differentiation between σ-hole and π-hole SpBs' natures more authentically. The complex energy frameworks were used to investigate noncovalent interactions. To better understand the different intermolecular interactions, we conducted a Hirshfeld surface, which revealed N···H (15.4%) and O···H (9.1%) contacts and Zn···O (5.1%) (SpBs).
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Active biological molecules present a powerful, yet largely untapped, opportunity to impart autonomous regulation to materials. Because these systems can function robustly to regulate when and where chemical reactions occur, they have the ability to bring complex, life-like behavior to synthetic materials. Here, we achieve this design feat by using functionalized circadian clock proteins, KaiB and KaiC, to engineer time-dependent crosslinking of colloids. The resulting material self-assembles with programmable kinetics, producing macroscopic changes in material properties, via molecular assembly of KaiB-KaiC complexes. We show that colloid crosslinking depends strictly on the phosphorylation state of KaiC, with kinetics that are synced with KaiB-KaiC complexing. Our microscopic image analyses and computational models indicate that the stability of colloidal super-structures depends sensitively on the number of Kai complexes per colloid connection. Consistent with our model predictions, a high concentration stabilizes the material against dissolution after a robust self-assembly phase, while a low concentration allows circadian oscillation of material structure. This work introduces the concept of harnessing biological timers to control synthetic materials; and, more generally, opens the door to using protein-based reaction networks to endow synthetic systems with life-like functional properties.
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The classical pathway (CP) is a potent mechanism for initiating complement activity and is a driver of pathology in many complement-mediated diseases. The CP is initiated via activation of complement component C1, which consists of the pattern recognition molecule C1q bound to a tetrameric assembly of proteases C1r and C1s. Enzymatically active C1s provides the catalytic basis for cleavage of the downstream CP components, C4 and C2, and is therefore an attractive target for therapeutic intervention in CP-driven diseases. Although an anti-C1s mAb has been Food and Drug Administration approved, identifying small-molecule C1s inhibitors remains a priority. In this study, we describe 6-(4-phenylpiperazin-1-yl)pyridine-3-carboximidamide (A1) as a selective, competitive inhibitor of C1s. A1 was identified through a virtual screen for small molecules that interact with the C1s substrate recognition site. Subsequent functional studies revealed that A1 dose-dependently inhibits CP activation by heparin-induced immune complexes, CP-driven lysis of Ab-sensitized sheep erythrocytes, CP activation in a pathway-specific ELISA, and cleavage of C2 by C1s. Biochemical experiments demonstrated that A1 binds directly to C1s with a Kd of â¼9.8 µM and competitively inhibits its activity with an inhibition constant (Ki) of â¼5.8 µM. A 1.8-Å-resolution crystal structure revealed the physical basis for C1s inhibition by A1 and provided information on the structure-activity relationship of the A1 scaffold, which was supported by evaluating a panel of A1 analogs. Taken together, our work identifies A1 as a new class of small-molecule C1s inhibitor and lays the foundation for development of increasingly potent and selective A1 analogs for both research and therapeutic purposes.
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Complemento C1s , Vía Clásica del Complemento , Animales , Ovinos , Péptido Hidrolasas , Complemento C1/metabolismo , Endopeptidasas , Piridinas/farmacologíaRESUMEN
A rare example of visible-light-mediated diverse reactivity of N-sulfinylamines with different types of carbene precursors has been disclosed. Acylsilanes and aryldiazoacetates have been utilized as nucleophilic and electrophilic carbene precursors into the NâSâO linchpin, to achieve valuable amides and α-iminoesters, respectively. Interestingly, diazocarbonyls can also participate in the amidation reaction with N-sulfinylamines via in situ generated ketenes. This operationally simple modular method offers a mild, transition-metal-free, and coupling-reagent-free protocol to fabricate structurally diverse amides and a promptly accessible technique to achieve α-iminoesters, where visible light remains as a key promoter.
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Female insects belonging to the genera Anopheles, Aedes, Glossina, and Rhodnius account for the majority of global vector-borne disease mortality. In response to mating, these female insects undergo several molecular, physiological, and behavioral changes. Studying the dynamic post-mating molecular responses in these insects that transmit human diseases can lead to the identification of potential targets for the development of novel vector control methods. With the continued advancements in bioinformatics tools, we now have the capability to delve into various physiological processes in these insects. Here, we discuss the availability of multiple datasets describing the reproductive physiology of the common blood-feeding insects at the molecular level. Additionally, we compare the male-derived triggers transferred during mating to females, examining both shared and species-specific factors. These triggers initiate post-mating genetic responses in female vectors, affecting not only their reproductive success but also disease transmission.
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We develop a framework to understand the mechanics of metamaterial sheets on curved surfaces. Here we have constructed a continuum elastic theory of mechanical metamaterials by introducing an auxiliary, scalar gauge-like field that absorbs the strain along the soft mode and projects out the stiff ones. We propose a general form of the elastic energy of a mechanism based metamaterial sheet and specialize to the cases of dilational metamaterials and shear metamaterials conforming to positively and negatively curved substrates in the Föppl-Von Kármán limit of small strains. We perform numerical simulations of these systems and obtain good agreement with our analytical predictions. This work provides a framework that can be easily extended to explore non-linear soft modes in metamaterial elasticity in future.
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We study the intricate interplay between ecological and evolutionary processes through the lens of the prisoner's dilemma game. But while previous studies on cooperation amongst selfish individuals often assume instantaneous interactions, we take into consideration delays to investigate how these might affect the causes underlying prosocial behavior. Through analytical calculations and numerical simulations, we demonstrate that delays can lead to oscillations, and by incorporating also the ecological variable of altruistic free space and the evolutionary strategy of punishment, we explore how these factors impact population and community dynamics. Depending on the parameter values and the initial fraction of each strategy, the studied eco-evolutionary model can mimic a cyclic dominance system and even exhibit chaotic behavior, thereby highlighting the importance of complex dynamics for the effective management and conservation of ecological communities. Our research thus contributes to the broader understanding of group decision-making and the emergence of moral behavior in multidimensional social systems.
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Cristalino , Lentes , Humanos , Altruismo , Evolución Biológica , Toma de DecisionesRESUMEN
Multiple rounds of DNA replication take place in various stages of the life cycle in the human malaria parasite Plasmodium falciparum. Previous bioinformatics analysis has shown the presence of putative Autonomously Replicating Sequence (ARS) like sequences in the Plasmodium genome. However, the actual sites and frequency of replication origins in the P. falciparum genome based on experimental data still remain elusive. Minichromosome maintenance (MCM) proteins are recruited by the Origin recognition complex (ORC) to the origins of replication in eukaryotes including P. falciparum. We used PfMCM6 for chromatin immunoprecipitation followed by sequencing (ChIP-seq) in the quest for identification of putative replication origins in the parasite. PfMCM6 DNA binding sites annotation revealed high enrichment at exon regions. This is contrary to higher eukaryotes that show an inclination of origin sites towards transcriptional start sites. ChIP-seq results were further validated by ChIP-qPCR results as well as nascent strand abundance assay at the selected PfMCM6 enriched sites that also showed preferential binding of PfORC1 suggesting potential of these sites as origin sites. Further, PfMCM6 ChIP-seq data showed a positive correlation with previously published histone H4K8Ac genome-wide binding sites but not with H3K9Ac sites suggesting epigenetic control of replication initiation sites in the parasites. Overall, our data show the genome-wide distribution of PfMCM6 binding sites with their potential as replication origins in this deadly human pathogen that not only broadens our knowledge of parasite DNA replication and its unique biology, it may help to find new avenues for intervention processes.
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Malaria Falciparum , Parásitos , Animales , Humanos , Plasmodium falciparum/genética , Parásitos/genética , Parásitos/metabolismo , Replicación del ADN/genética , Sitios de Unión , Malaria Falciparum/genética , Cromosomas/metabolismo , Componente 6 del Complejo de Mantenimiento de Minicromosoma/genética , Componente 6 del Complejo de Mantenimiento de Minicromosoma/metabolismoRESUMEN
Borrelial pathogens are vector-borne etiological agents known to cause Lyme disease, relapsing fever, and Borrelia miyamotoi disease. These spirochetes each encode several surface-localized lipoproteins that bind components of the human complement system to evade host immunity. One borrelial lipoprotein, BBK32, protects the Lyme disease spirochete from complement-mediated attack via an alpha helical C-terminal domain that interacts directly with the initiating protease of the classical complement pathway, C1r. In addition, the B. miyamotoi BBK32 orthologs FbpA and FbpB also inhibit C1r, albeit via distinct recognition mechanisms. The C1r-inhibitory activities of a third ortholog termed FbpC, which is found exclusively in relapsing fever-causing spirochetes, remains unknown. Here, we report the crystal structure of the C-terminal domain of Borrelia hermsii FbpC to a limiting resolution of 1.5 Å. We used surface plasmon resonance and assays of complement function to demonstrate that FbpC retains potent BBK32-like anticomplement activities. Based on the structure of FbpC, we hypothesized that conformational dynamics of the complement inhibitory domains of borrelial C1r inhibitors may differ. To test this, we utilized the crystal structures of the C-terminal domains of BBK32, FbpA, FbpB, and FbpC to carry out molecular dynamics simulations, which revealed borrelial C1r inhibitors adopt energetically favored open and closed states defined by two functionally critical regions. Taken together, these results advance our understanding of how protein dynamics contribute to the function of bacterial immune evasion proteins and reveal a surprising plasticity in the structures of borrelial C1r inhibitors.
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Proteínas Bacterianas , Borrelia , Proteínas Inactivadoras del Complemento 1 , Enfermedad de Lyme , Fiebre Recurrente , Humanos , Proteínas Bacterianas/química , Enfermedad de Lyme/inmunología , Enfermedad de Lyme/microbiología , Fiebre Recurrente/inmunología , Fiebre Recurrente/microbiología , Proteínas Inactivadoras del Complemento 1/química , Dominios Proteicos , Cristalografía por Rayos XRESUMEN
In this article, we have synthesized two contemporary ortho-vanillin-based Salen-type ligands (H2L1/H2L2) characterized by modern spectroscopic tools. EDX analysis supports the elemental composition (C, N, O, and Br). SEM examined the morphology of the synthesized compounds. The molecular geometry was optimized in the gas phase using B3LYP-D3/6-311G (d, p) level. The global reactivity parameters, HOMO-LUMO energy gap (Δ), atomic properties, MESP, and ADME/T, vividly explore the chemical reactivity and toxicity of two Salen-type ligands. The DFT simulated IR/NMR characterized essential structural assignments, and UV-Visible spectra were employed to predict the optical properties. The article demonstrated in silico molecular docking against the Gm + ve Bacillus subtilis (6UF6), and Gm -ve Proteus Vulgaris establishes the ligand binding ability with essential amino acids through conventional H-bonding or other significant interactions. The docking simulation is compared for two compounds better than the control drugs and confirms the antimicrobial activity. The theoretical drug-like properties have been explored in-depth by ADME/T using the SWISSADME database. The analysis estimated the molecule's lipophilicity, the consensus P0/W, and water solubility. Thus, using various pharmaco-logical parameters, toxicity explains where the electron-withdrawing Br group plays a more toxic effect in H2L2 than in H2L1.
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This work contemplates synthesizing M-SCN crystal compounds (M = Hg/Pb/Cu) in the presence of respective metal salts and exogenous ancillary SCN- ion by slowly evaporating the mixed solvent (CH3OH + ACN). The complexes were characterized by spectroscopy, SEM/EDX, and X-ray crystallography. The Hg-Complex, Pb-Complex, and Cu-Complex crystallize in the monoclinic space group (Z = 2/4). The crystal packing fascinatingly consists of weak covalent bonding and Pbâ¯S contacts of tetrel type bond. Here are the incredible supramolecular topographies delineated by the Hirshfeld surface and 2D fingerprint plot. The B3LYP/6-311++G (d, p) level calculations in the gas phase optimized the compound's geometry. The energy difference (Δ) between HOMO-LUMO and global reactivity parameters investigates the complex's energetic activity. MESP highlights the electrophilic/nucleophilic sites and H-bonding interactions. Molecular docking was conceded with the Gram- + ve bacterium Bacillus Subtilis (PDB ID: 6UF6) and the Gram-ve bacterium Proteus Vulgaris (PDB ID: 5HXW) to authenticate the bactericidal activity. ADME/T explains the various pharmacological properties. In addition, we studied the antibacterial activity with MIC (µg/mL) values and time-kill kinetics against Staphylococcus aureus (ATCC 25923) and Bacillus subtilis (ATCC 6635) as Gram-positive, Pseudomonas aeruginosa (ATCC 27853) and Escherichia coli (ATCC 25922) as Gram-negative bacteria.