Competitive Inhibitor Research Articles

A new route to the synthesis of 2-hydrazolyl-4-thiazolidinone hybrids, evaluation of α-glucosidase inhibitory activity and molecular modeling insights

One of the multifactorial worldwide health syndromes is diabetes mellitus which is increasing at a disturbing rate. The inhibition of α-glucosidase, an enzyme that catalyzes starch hydrolysis in the intestine, is one helpful therapeutic approach for controlling hyperglycemia related to type-2 diabetes. To discover α-glucosidase inhibitors, some 2-hydrazolyl-4-thiazolidinone hybrids (3a-e) were synthesized from new one-pot reaction procedures. Next, their chemical structures were confirmed by 1H NMR, 13C NMR, and FT-IR spectra, and elemental analysis technique. Then, the α-glucosidase inhibitory activity of the titled compounds was evaluated. Among them, derivatives 3b and 3c revealed the highest activity against α-glucosidase compared to acarbose as a drug. Enzyme kinetic studies of the most active derivative (3b) indicated a competitive inhibition. Finally, molecular modeling studies were accomplished to describe vital interactions of the most potent compounds (3b and 3c) with the α-glucosidase enzyme.

Suppressing the side reactions of pregnenolone acetylation in transgenic yeast using competitive inhibition and optimal vector‒host system

Suppressing the side reactions of pregnenolone acetylation in transgenic yeast using competitive inhibition and optimal vector‒host system

Design, synthesis, molecular modeling, in vitro evaluation of novel piperidine-containing hydrazone derivatives as cholinesterase inhibitors.

In an effort to develop new and effective therapeutic agents for Alzheimer's disease, a series of hydrazone derivatives bearing piperidine rings have been designed and synthesized. The chemical structures of the compounds were characterized by various spectroscopic techniques. In vitro antioxidant and cholinesterase activities of the compounds were evaluated. Among the compounds, N12 exhibited the most antioxidant activity in all methods (CUPRAC, FRAP, DPPH, ABTS). In vitro acetylcholinesterase (AChE) activity results of the compounds showed good IC50 values between 14.124 ± 0.084 and 49.680 ± 0.110 µM were obtained (IC50 = 38.842 ± 0.053 µM for Donepezil). Among the compounds, N7 and N6 are much more effective derivatives than the standard compound donepezil with IC50 values of 14.124 ± 0.084 and 17.968 ± 0.072 µM, respectively. In vitro, butyrylcholinesterase (BChE) inhibition values of the compounds were between 13.505 ± 0.025 and 52.230 ± 0.027 μm. Among the compounds, N6 has the highest BChE inhibition with an IC50 value of 13.505 μm in the series. The cytotoxicity and AChE inhibitory activity of the compounds on SH-SY5Y cell lines were also evaluated. Kinetic studies were also performed to determine the behavior of the compounds as competitive or noncompetitive inhibitors. The binding modes of N6, which was determined to be highly effective according to in vitro analyses, with AChE and BChE were investigated using molecular docking studies, and the stability of the complexes was determined by molecular dynamics simulations. These findings indicated that AChE and BChE enzymes maintained their overall structural stability and compactness during interactions with compound N6.

Cotransport of Thallium(I) and kaolinite colloids in quartz sand media containing sodium humate: Ionic strength, pH and kaolinite colloid concentration

In real soil environments, humus, colloids and other components significantly affect pollutant migration behavior. Investigating Tl(I) and kaolinite colloids’ cotransport in quartz sand media containing sodium humate (HA-Na) is vital for comprehending Tl(I) migration underground. This study examined the migration of Tl(I) and kaolinite colloids across varying pH levels (5, 7), ionic strengths (ISs) (1, 5, 50 mmol/L), and kaolinite colloid concentrations. Results indicate that lower IS and pH promote Tl(I) migration when transported alone. In cotransport system, kaolinite promotes Tl(I) migration under acidic conditions but inhibits it under neutral conditions, except at high kaolinite concentrations, where the effect shifts from inhibition to promotion. This is primarily due to changes in the zeta potential of quartz sand, HA-Na, and kaolinite, as well as Tl(I) adsorption after HA-Na and kaolinite occupy binding sites. Competitive adsorption between cations and Tl(I) also plays a significant role. Conversely, in individual system, higher IS and pH inhibit kaolinite migration, while increased kaolinite concentration promotes it. In cotransport system, Tl(I) promotes kaolinite migration under acidic conditions but inhibits it under neutral conditions, except at low kaolinite concentrations. This relates to changes in the zeta potential between kaolinite and the medium, as well as the retention of HA-Na in the column and its adsorption onto kaolinite. Competitive adsorption and binding site saturation also have an impact. This study enhances understanding of Tl(I) migration by revealing the dual effect of kaolinite colloids under different environmental conditions, contributing to better knowledge of Tl(I) fate and transport in natural environments.

Inhibition of BCAT1-mediated cytosolic leucine metabolism regulates Th17 responses via the mTORC1-HIF1α pathway

Branched-chain amino acids (BCAAs), particularly leucine, are indispensable AAs for immune regulation through metabolic rewiring. However, the molecular mechanism underlying this phenomenon remains unclear. Our investigation revealed that T-cell receptor (TCR)-activated human CD4+ T cells increase the expression of BCAT1, a cytosolic enzyme responsible for BCAA catabolism, and SLC7A5, a major BCAA transporter. This upregulation facilitates increased leucine influx and catabolism, which are particularly crucial for Th17 responses. Activated CD4+ T cells induce an alternative pathway of cytosolic leucine catabolism, generating a pivotal metabolite, β-hydroxy β-methylbutyric acid (HMB), by acting on BCAT1 and 4-hydroxyphenylpyruvate dioxygenase (HPD)/HPD-like protein (HPDL). Inhibition of BCAT1-mediated cytosolic leucine metabolism, either with BCAT1 inhibitor 2 (Bi2) or through BCAT1, HPD, or HPDL silencing using shRNA, attenuates IL-17 production, whereas HMB supplementation abrogates this effect. Mechanistically, HMB contributes to the regulation of the mTORC1-HIF1α pathway, a major signaling pathway for IL-17 production, by increasing the mRNA expression of HIF1α. This finding was corroborated by the observation that treatment with L-β-homoleucine (LβhL), a leucine analog and competitive inhibitor of BCAT1, decreased IL-17 production by TCR-activated CD4+ T cells. In an in vivo experimental autoimmune encephalomyelitis (EAE) model, blockade of BCAT1-mediated leucine catabolism, either through a BCAT1 inhibitor or LβhL treatment, mitigated EAE severity by decreasing HIF1α expression and IL-17 production in spinal cord mononuclear cells. Our findings elucidate the role of BCAT1-mediated cytoplasmic leucine catabolism in modulating IL-17 production via HMB-mediated regulation of mTORC1-HIF1α, providing insights into its relevance to inflammatory conditions.

The Inferential Binding Sites of GCGR for Small Molecules Using Protein Dynamic Conformations and Crystal Structures.

Glucagon receptor (GCGR) is a class B1 G-protein-coupled receptor that plays a crucial role in maintaining human blood glucose homeostasis and is a significant target for the treatment of type 2 diabetes mellitus (T2DM). Currently, six small molecules (Bay 27-9955, MK-0893, MK-3577, LY2409021, PF-06291874, and LGD-6972) have been tested or are undergoing clinical trials, but only the binding site of MK-0893 has been resolved. To predict binding sites for other small molecules, we utilized both the crystal structure of the GCGR and MK-0893 complex and dynamic conformations. We docked five small molecules and selected the best conformation based on binding mode, docking score, and binding free energy. We performed MD simulations to verify the binding mode of the selected small molecules. Moreover, when selecting conformations, results of competitive binding were referred to. MD simulation indicated that Bay 27-9955 exhibits moderate binding stability in Pocket 3. MK-3577, LY2409021, and PF-06291874 exhibited highly stable binding to Pocket 2, consistent with experimental results. However, LY2409021 may also bind to Pocket 5. Additionally, LGD-6972 exhibited relatively stable binding in Pocket 5. We also conducted structural modifications of LGD-6972 based on the results of MD simulations and predicted its analogues' bioavailability, providing a reference for the study of GCGR small molecules.

PUM1-TRAF3 fusion protein activates non-canonical NF-κB signaling via rescued NIK in biliary tract cancer

Discovery and verification of diagnostic or therapeutic biomarkers for biliary tract cancer (BTC) is challenging owing to the low prevalence of the disease. Here, we identified and investigated the clinical impact of a fusion gene, Pumilio1-tumor necrosis factor receptor-associated factor 3 (PUM1-TRAF3), caused by 1;14 chromosomal translocation in BTC. PUM1-TRAF3 was initially identified in the RNA-sequencing of five BTC surgical tissues and confirmed by fluorescence in situ hybridization. Expression of the fusion gene was validated in an expanded cohort (5/55, 9.1%). Establishment and molecular assessment of PUM1-TRAF3 expressing BTC cells revealed that PUM1-TRAF3 activates non-canonical NF-κB signaling via NF-κB-inducing kinase (NIK). Abnormal TRAF3 activity, driven by competitive binding of PUM1-TRAF3 and TRAF3 to NIK, led to NIK rescue followed by P52/RelB nuclear translocation, all of which were reverted by an NIK inhibitor. The elevated expression of NIK and activated NF-κB signaling was observed in the PUM1-TRAF3-expressing regions of patient tissues. Expression of the PUM1-TRAF3 fusion was significantly correlated with strong NIK expression, which is associated with a poorer prognosis for patients with BTC. Overall, our study identifies a new fusion gene, PUM1-TRAF3, that activates NIK and non-canonical NF-κB signaling, which may be beneficial for developing precise treatment strategies for BTC.

Inhibitory activities of Aruncus dioicus alkaloidal glycosides against protein tyrosine phosphatase 1B and α-glucosidase: A methodical theory-experiment investigation

Objective: Aruncus dioicus has been known by the scientific literature and folk experiences for its diverse biological activities, including anti-hyperglycemic effects. Methodology: The aerial parts of the plant collected from Quan Lan Island (Vietnam) were subjected to a methodical theory-experiment investigation for its chemical composition and biological potentials. Results: Firstly, experimental isolation and spectroscopic characterization identified the compositional compounds, ie sambunigrin (1), prunasin (2), uridine (3), and adenosine (4). Secondly, their elucidated structures were predicted with promising bio-chemo-pharmacological potentiality by different computational platforms, ie: docking simulation (docking scores < 10 kcal.mol−1); quantum calculation (dipole moments < 3 Debye); QSARIS model (satisfying Lipinski's rule of five); SwissADME model (satisfying Pires’ interpretations). Finally, the compounds (1-4) were under accumulative purification and in vitro tests against diabetes-related enzymes, ie: protein tyrosine phosphatase 1B (1 with lowest IC50 value 0.39 ± 0.26 μM, 2 with no activity) and α-glucosidase (1 with lowest IC50 value 44.89 ± 0.93 μM, 2 with no activity); also, the inhibitory kinetics based on Lineweaver-Burk and Dixon plot experiments revealed the competitive inhibition mode of 1 against PTP1B ( Ki value 0.49 μM). Conclusions: Altogether, the results obtained suggest that A. dioicus and its bioactive compounds, especially sambunigrin (1), uridine (3), and adenosine (4), could be considered as a natural source for further research and development of anti-diabetic agents.

Competitive Binding Kinetics of Methylmercury-Cysteine with Dissolved Organic Matter: Critical Impacts of Thiols on Adsorption and Uptake of Methylmercury by Algae.

Complexes with low-molecular-weight thiols are crucial species of methylmercury (MeHg) excreted by anaerobic Hg-methylating microbes, notably, MeHg-cysteine (MeHg-Cys). As MeHg-Cys diffuses into surface water, it would undergo a ligand exchange process with dissolved organic matter (DOM) under nonsulfidic conditions, inevitably altering MeHg speciation and bioavailability to phytoplankton. In this study, we investigated the competitive binding kinetics between MeHg-Cys and Suwannee River natural organic matter, and their influence on the adsorption and uptake of MeHg by the cyanobacterium, Synechocystis sp. PCC6803. Liquid chromatography-inductively coupled plasma mass spectrometry was employed to monitor the kinetics processes involving competition of DOM with Cys for MeHg binding, which revealed that competitive binding kinetics were dictated by the abundance of thiol moieties in DOM. Thiol concentrations of 0.97 and 49.34 μmol of thiol (g C)-1 resulted in competitive binding rate constant (k values) of 0.30 and 3.47 h-1, respectively. Furthermore, the time-dependent competitive binding of DOM toward MeHg-Cys significantly inhibited MeHg adsorption and uptake by cyanobacteria, an effect that was amplified by an increased thiol abundance in DOM. These findings offer valuable insights into the kinetic characteristics of MeHg's fate and transport, as well as their impact on bioconcentration in aquatic organisms within natural aquatic ecosystems.

Interaction of Cephalosporins with Human Serum Albumin: A Structural Study.

Modification of the R1 and R2 side chain structures has been used as the main strategy to expand the spectrum of cephalosporins and impart resistance to hydrolysis by β-lactamases. These structural modifications also result in a wide range of plasma protein binding, especially with human serum albumin (HSA). Here, we determined the crystal structures of the HSA complexes with two clinically important cephalosporins, ceftriaxone and cefazolin, and evaluated the binding of cephalosporin to HSA by susceptibility testing and competitive binding assay. Ceftriaxone and cefazolin bind to subdomain IB of HSA, and their cephem core structures are recognized by Arg117 of HSA. Tyr161 of HSA changes its rotamer depending on the cephalosporin, resulting in alterations of the cavity shape occupied by the R2 side chain of cephalosporins. These findings provide structural insight into the mechanisms underlying the HSA binding of cephalosporins.

OBP83b and OBP49a Involved in the Perception of Female-Derived Pheromones in Bactrocera dorsalis (Hendel).

In Bactrocera dorsalis, both males and females release chemical signals to attract mates. In our previous study, we identified ethyl laurate, ethyl myristate, and ethyl palmitate as potent female-derived pheromones that contribute to mate attraction. However, the mechanisms underlying the olfactory recognition remain unclear. In this study, we observed strong antennal and behavioral responses in male B. dorsalis to these female-derived pheromones, and further investigation revealed significant upregulation of OBP49a and OBP83b following exposure to these compounds. Through fluorescence competitive binding assays and RNA interference techniques, we demonstrated the crucial roles of OBP49a and OBP83b in detecting female-derived pheromones. Finally, molecular docking analysis identified key residues, including His134 in OBP83b and a lysine residue in OBP49a, which formed hydrogen bonds with female-derived pheromones, facilitating their binding. These findings not only advance our understanding of olfactory recognition of pheromones in B. dorsalis but also offer potential targets for developing olfaction-interfering techniques for pest control.

Interactions between Inhibitors and 5-Lipoxygenase: Insights from Gaussian Accelerated Molecular Dynamics and Markov State Models.

Inflammation is a protective stress response triggered by external stimuli, with 5-lipoxygenase (5LOX) playing a pivotal role as a potent mediator of the leukotriene (Lts) inflammatory pathway. Nordihydroguaiaretic acid (NDGA) functions as a natural orthosteric inhibitor of 5LOX, while 3-acetyl-11-keto-β-boswellic acid (AKBA) acts as a natural allosteric inhibitor targeting 5LOX. However, the precise mechanisms of inhibition have remained unclear. In this study, Gaussian accelerated molecular dynamics (GaMD) simulation was employed to elucidate the inhibitory mechanisms of NDGA and AKBA on 5LOX. It was found that the orthosteric inhibitor NDGA was tightly bound in the protein's active pocket, occupying the active site and inhibiting the catalytic activity of the 5LOX enzyme through competitive inhibition. The binding of the allosteric inhibitor AKBA induced significant changes at the distal active site, leading to a conformational shift of residues 168-173 from a loop to an α-helix and significant negative correlated motions between residues 285-290 and 375-400, reducing the distance between these segments. In the simulation, the volume of the active cavity in the stable conformation of the protein was reduced, hindering the substrate's entry into the active cavity and, thereby, inhibiting protein activity through allosteric effects. Ultimately, Markov state models (MSM) were used to identify and classify the metastable states of proteins, revealing the transition times between different conformational states. In summary, this study provides theoretical insights into the inhibition mechanisms of 5LOX by AKBA and NDGA, offering new perspectives for the development of novel inhibitors specifically targeting 5LOX, with potential implications for anti-inflammatory drug development.

Docking, MD Simulations, and DFT Calculations: Assessing W254's Function and Sartan Binding in Furin.

Furins are serine endoproteases that are involved in many biological processes, where they play important roles in normal metabolism, in the activation of various pathogens, while they are a target for therapeutic intervention. Dichlorophenyl-pyridine "BOS" compounds are well known drugs that are used as inhibitors of human furin by an induced-fit mechanism, in which tryptophan W254 in the furin catalytic cleft acts as a molecular transition energy gate. The binding of "BOS" drug into the active center of furin has been computationally studied using the density functional theory (DFT) and ONIOM multiscaling methodologies. The binding enthalpies of the W254 with the furin-BOS is -32.8 kcal/mol ("open") and -18.8 kcal/mol ("closed"), while the calculated torsion barrier was found at 30 kcal/mol. It is significantly smaller than the value of previous MD calculations due to the relaxation of the environment, i.e., nearby groups of the W254, leading to the reduction of the energy demands. The significant lower barrier explains the experimental finding that the dihedral barrier of W254 is overcome. Furthermore, sartans were studied to evaluate their potential as furin inhibitors. Sartans are AT1 antagonists, and they effectively inhibit the hypertensive effects induced by the peptide hormone Angiotensin II. Here, they have been docked into the cavity to evaluate their effect on the BOS ligand via docking and molecular dynamics simulations. A consistent binding of sartans within the cavity during the simulation was found, suggesting that they could act as furin inhibitors. Finally, sartans interact with the same amino acids as W254, leading to a competitive binding that may influence the pharmacological efficacy and potential drug interactions of sartans.

Monovalent, bivalent and biparatopic nanobodies targeting S1 protein of porcine epidemic diarrhea virus efficiently neutralized the virus infectivity

BackgroundPorcine epidemic diarrhea virus (PEDV) is a highly contagious coronavirus that causes severe diarrhea and death in neonatal piglets, which has brought huge economic losses to the pork industry worldwide since its first discovery in the early 1970s in Europe. Passive immunization with neutralizing antibodies against PEDV is an effective prevention measure. To date, there are no effective therapeutic drugs to treat the PEDV infection.ResultsWe conducted a screening of specific nanobodies against the S1 protein from a phage display library obtained from immunized alpacas. Through competitive binding to antigenic epitopes, we selected instead of chose nanobodies with high affinity and constructed a multivalent tandem. These nanobodies were shown to inhibit PEDV infectivity by the neutralization assay. The antiviral capacity of nanobody was found to display a dose-dependent pattern, as demonstrated by IFA, TCID50, and qRT-PCR analyses. Notably, biparatopic nanobody SF-B exhibited superior antiviral activity. Nanobodies exhibited low cytotoxicity and high stability even under harsh temperature and pH conditions, demonstrating their potential practical applicability to animals.ConclusionsNanobodies exhibit remarkable biological properties and antiviral effects, rendering them a promising candidate for the development of anti-PEDV drugs.

Galectin-3 contributes to pathogenesis of IgA nephropathy

IgA nephropathy (IgAN) is the most common type of glomerulonephritis that frequently progresses to kidney failure. However, the molecular pathogenesis underlying IgAN remains largely unknown. Here, we investigated the role of galectin-3 (Gal-3), a galactoside-binding protein in IgAN pathogenesis and showed that Gal-3 expression by the kidney was significantly enhanced in patients with IgAN. In both TEPC-15 hybridoma-derived IgA-induced, passive, and spontaneous “grouped” ddY IgAN models, Gal-3 expression was clearly increased with disease severity in the glomeruli, peri-glomerular regions, and some kidney tubules. Gal-3 knockout (KO) in the passive IgAN model had significantly improved proteinuria, kidney function and reduced severity of kidney pathology, including neutrophil infiltration and decreased differentiation of Th17 cells from kidney-draining lymph nodes, despite increased percentages of regulatory T cells. Gal-3 KO also inhibited the NLRP3 inflammasome, yet it enhanced autophagy and improved kidney inflammation and fibrosis. Moreover, administration of 6-de-O-sulfated, N-acetylated low-molecular-weight heparin, a competitive Gal-3 binding inhibitor, restored kidney function and improved kidney lesions in passive IgAN mice. Thus, our results suggest that Gal-3 is critically involved in IgAN pathogenesis by activating the NLRP3 inflammasome and promoting Th17 cell differentiation. Hence, targeting Gal-3 action may represent a new therapeutic strategy for treatment of this kidney disease.

Synthesis of 1,2,3-triazole functionalized derivatives of metronidazole as potent inhibitors of urease: Synthesis via click chemistry, in vitro urease inhibition, kinetics and molecular docking studies

Current study is based on multistep synthesis of sixteen new 1,2,3-triazole functionalized derivatives of metronidazole drug 3–18 by using a Cu(I)-catalysed 1,3-dipolar azide-alkyne cycloaddition (CuAAC) reaction via a click chemistry approach. All the compounds were purified by using conventional silica gel column chromatography with isocratic eluent. Their structures were confirmed by using various spectroscopic techniques including UV, IR, LR and HR MS, 1H-, 13CNMR , and 2D-NMR spectroscopy. The library of 1,2,3-triazole derivatives of metronidazole 3–18 was evaluated for urease inhibitory activity, and cytotoxicity against normal cells. Compound 8 (IC50= 6.8 ± 0.8 µM) was found to be the most potent urease inhibitor, while acetohydroxamic acid (IC50 = 20.3 ± 0.4 µM) was used as experimental standard. Compounds 5 (IC50 = 7.9 ± 0.9 µM), 6 (IC50 = 9.5 ± 0.2 µM), 7 (IC50 = 8.5 ± 1.0 µM), 10 (IC50 = 9.3 ± 1.1 µM), and 18 (IC50 = 7.2 ± 0.6 µM) were also found to be potent inhibitors of urease. Parent drug metronidazole also showed a potent urease enzyme inhibitory activity with IC50= 10.54 ± 0.8 µM. All compounds were found to be non-cytotoxic against the human fibroblast (B.J.) cell line. Molecular docking and kinetic studies were performed for compounds 5–8, 10, and 18 which showed that these compounds are competitive inhibitors of urease enzyme inhibition. Urease inhibition is a therapeutic approach to help in the treatment of peptic ulcers, caused by ureolytic bacteria. The initial findings presented herein therefore, deserve further studies.

One-Pot Self-Assembly of Sequence-Controlled Mesoporous Heterostructures via Structure-Directing Agents.

Multimaterial heterostructures have led to characteristics surpassing the individual components. Nature controls the architecture and placement of multiple materials through biomineralization of nanoparticles (NPs); however, synthetic heterostructure formation remains limited and generally departs from the elegance of self-assembly. Here, a class of block polymer structure-directing agents (SDAs) are developed containing repeat units capable of persistent (covalent) NP interactions that enable the direct fabrication of nanoscale porous heterostructures, where a single material is localized at the pore surface as a continuous layer. This SDA binding motif (design rule 1) enables sequence-controlled heterostructures, where the composition profile and interfaces correspond to the synthetic addition order. This approach is generalized with 5 material sequences using an SDA with only persistent SDA-NP interactions ("P-NP1-NP2"; NPi = TiO2, Nb2O5, ZrO2). Expanding these polymer SDA design guidelines, it is shown that the combination of both persistent and dynamic (noncovalent) SDA-NP interactions ("PD-NP1-NP2") improves the production of uniform interconnected porosity (design rule 2). The resulting competitive binding between two segments of the SDA (P- vs D-) requires additional time for the first NP type (NP1) to reach and covalently attach to the SDA (design rule 3). The combination of these three design rules enables the direct self-assembly of heterostructures that localize a single material at the pore surface while preserving continuous porosity.

Synthesis, α-glucosidase inhibitory activity, and molecular dynamic simulation of 6-chloro-2-methoxyacridine linked to triazole derivatives

Α-glucosidase inhibition can be useful in the management of carbohydrate-related diseases, especially type 2 diabetes mellitus. Therefore, in this study, a new series of 6-chloro-2-methoxyacridine bearing different aryl triazole derivatives were designed, synthesized, and evaluated as potent α-glucosidase inhibitors. The most potent derivative in this group was 7h bearing para-fluorine with IC50 values of 98.0 ± 0.3 µM compared with standard drug acarbose (IC50 value = 750.0 ± 10.5 μM). A kinetic study of compound 7h revealed that it is a competitive inhibitor against α-glucosidase. Molecular dynamic simulations of the most potent derivative were also executed and indicated suitable interactions with residues of the enzyme which rationalized the in vitro results.

Comparing amoxicillin and trimethoprim: Overall performance in combating Escherichia coli-causing urinary tract infection

Urinary Tract Infection (UTI) is one of the most prevalent bacterial infections in the world, and 80% of reported UTI cases are derived by gram negative bacteria Escherichia coli. Uropathogenic Escherichia coli is strongly adaptive and resilient against immune response, forming Intracellular Bacterial Communities (IBC) inside uroepithelium cells that constitute the urethra and the bladder. Their rapid absorption of cellular nutrients enables them to advance upward toward the kidney and cause inflammation. Hence, based on the perceived severity of UTI, multiple antibiotics are used to treat UPEC-causing UTI. This article provides a detailed review on the contemporary performance of amoxicillin and trimethoprim, both widely used to treat UPEC-causing UTI for decades. Amoxicillin is a penicillin-derivative that produces bactericidal by inhibiting transpeptidase to disrupt peptidoglycan synthesis, causing rapid-growing bacteria to lyse. It is a well-tolerated drug that can be used on pregnant patients. Resistant UPEC develop beta-lactamase to counter amoxicillin. Trimethoprim, on the other hand, is a dihydropyrimidine antibiotic that impedes the production of tetrahydrofolic acids, producing either bacteriostatic or bactericidal effects. Resistant UPEC transforms the shape of tetrahydrofolic acids-producing enzyme, dihydrofolic reductase, to resist trimethoprim. Although amoxicillin and trimethoprim are competitive inhibitors are effective against a variety of gram-positive and gram-negative species, trimethoprim, in statistical study, is proven to be more effective than amoxicillin in treating gram-negative UTI. Today, the wide-spread resistant strains of UPEC exists for both drugs. Thus, amoxicillin and trimethoprim are implemented mainly through combination therapies, amoxicillin/clavulanate and trimethoprim sulfamethoxazole, respectively. These combinations are more effective than the drugs to be used alone and are able to counter some resistant strains, but UPEC that are resistant to combinations also exists. Regardless, both amoxicillin and trimethoprim are still used as first-line antibiotics, while more powerful antibiotics are reserved for special multi-resistant superbugs.

Inhibition of protein tyrosine phosphatase 1B by serratane triterpenes from Huperzia serrata and their molecular docking study

During the search for protein tyrosine phosphatase 1B (PTP1B) inhibitory compounds from the natural resources, two new serratane triterpenes, 3-O-dihydro-p-coumaroyltohogenol (1) and 21-O-acetyltohogenol (2), along with four known serratane triterpenes (3–6), were isolated from the whole plant of Huperzia serrata. The chemical structures of compounds 1 and 2 were determined by NMR study, HRMS analysis, and chemical modification. All isolates were evaluated for their PTP1B inhibitory activities. Among the isolates, compounds 1, 3, 5 and 6 exhibit moderate inhibitory activities against PTP1B. Kinetic studies demonstrated that they are competitive inhibitors. Molecular docking studies support these experimental results by showing that compounds 1, 3, 5 and 6 interact with the active site of PTP1B, clarifying the structure–activity relationship. This study suggests that serratane triterpenes from H. serrata have potential as starting skeletons for anti-diabetes or anti-obesity agents.