Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Dimeric ?-AApeptides With Potent and Selective Antibacterial Activity.

ABSTRACT: Over the past few decades, the emergence of antibiotic resistance developed by life-threatening bacteria has become increasingly prevalent. Thus, there is an urgent demand to develop novel antibiotics capable of mitigating this trend. Herein, we report a series of dimeric ?-AApeptide derivatives as potential antibiotic agents with limited toxicity and excellent selectivity against Gram-positive strains. Among them, compound 2 was identified to have the best MICs without inducing drug resistance, even after exposure to MRSA for 20 passages. Time-kill kinetics and mechanistic studies suggested that 2 could mimic host-defense peptides (HDPs) and rapidly eradicate MRSA within 2 hours through disturbing the bacteria membrane. Meanwhile, biofilm formation was successfully inhibited even at a low concentration. Taken together, these results suggested the great potential of dimeric ?-AApeptide derivatives as antibacterial agents.

SUBMITTER: Wang M

PROVIDER: S-EPMC7304243 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Dimeric γ-AApeptides With Potent and Selective Antibacterial Activity.

Wang Minghui M Gao Ruixuan R Sang Peng P Odom Timothy T Zheng Mengmeng M Shi Yan Y Xu Hai H Cao Chuanhai C Cai Jianfeng J

Frontiers in chemistry 20200612

Over the past few decades, the emergence of antibiotic resistance developed by life-threatening bacteria has become increasingly prevalent. Thus, there is an urgent demand to develop novel antibiotics capable of mitigating this trend. Herein, we report a series of dimeric γ-AApeptide derivatives as potential antibiotic agents with limited toxicity and excellent selectivity against Gram-positive strains. Among them, compound <b>2</b> was identified to have the best MICs without inducing drug resi ...[more]

PMID: 32596202

Similar Datasets

Identification of ?-AApeptides with potent and broad-spectrum antimicrobial activity.

Project description:We report the identification of a new class of antimicrobial peptidomimetics-?-AApeptides with potent and broad-spectrum activity, including clinically-relevant strains that are unresponsive to most antibiotics. They are also not prone to select for drug-resistance.

| S-EPMC3746764 | biostudies-literature

Potent antibacterial activity of MXene-functionalized graphene nanocomposites.

Project description:Two dimensional (2D) nanomaterials display properties with significant biological utility (e.g., antimicrobial activity). In this study, MXene-functionalized graphene (FG) nanocomposites with Ti3C2T x in varying ratios (FG : Ti3C2T x , 25 : 75%, 50 : 50%, and 75 : 25%) were prepared and characterized via scanning electron microscopy, scanning electron microscopy-energy dispersive X-ray (SEM-EDX), high-resolution transmission electron microscopy (HRTEM), and zeta potential analysis. Their cytotoxicity was assessed using immortalized human keratinocytes (HaCaT) cells at three different timepoints, and antibacterial activity was assessed using Gram-positive Methicillin resistant Staphylococcus aureus, MRSA, and Gram-negative neuro-pathogenic Escherichia coli K1 (E. coli K1) in vitro. The nanomaterials and composites displayed potent antibacterial effects against both types of bacteria and low cytotoxicity against HaCaT cells at 200 μg mL-1, which is promising for their utilization for biomedical applications.

| S-EPMC9673471 | biostudies-literature

Highly Potent, Stable, and Selective Dimeric Hetarylpropylguanidine-Type Histamine H<sub>2</sub> Receptor Agonists.

Project description:On the basis of the long-known prototypic pharmacophore 3-(1H-imidazol-4-yl)propylguanidine (SK&F 91486, 2), monomeric, homodimeric, and heterodimeric bisalkylguanidine-type histamine H2 receptor (H2R) agonists with various alkyl spacers were synthesized. Aiming at increased H2R selectivity of the ligands, the imidazol-4-yl moiety was replaced by imidazol-1-yl, 2-aminothiazol-5-yl or 2-amino-4-methylthiazol-5-yl according to a bioisosteric approach. All compounds turned out to be partial or full agonists at the h/gp/rH2R. The most potent analogue, the thiazole-type heterodimeric ligand 63 (UR-Po461), was a partial agonist (Emax = 88%) and 250 times more potent than histamine (pEC50: 8.56 vs 6.16, gpH2R, atrium). The homodimeric structures 56 (UR-Po395) and 58 (UR-Po448) exhibited the highest hH2R affinities (pKi: 7.47, 7.33) in binding studies. Dimeric amino(methyl)thiazole derivatives, such as 58, generated an increased hH2R selectivity compared to the monomeric analogues, e.g., 139 (UR-Po444). Although monomeric ligands showed up lower affinities and potencies at the H2R, compounds with a short alkylic side chain like 129 (UR-Po194) proved to be highly affine hH4R ligands.

| S-EPMC6130797 | biostudies-literature

Kisameet Clay Exhibits Potent Antibacterial Activity against the ESKAPE Pathogens.

Project description:UNLABELLED:The ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens cause an increasing number of nosocomial infections worldwide since they escape the inhibitory effect of the available antibiotics and the immune response. Here, we report the broad-spectrum and potent antibacterial activity of Kisameet clay, a natural clay mineral from British Columbia, Canada, against a group of multidrug-resistant ESKAPE strains. The results suggest that this natural clay might be developed as a therapeutic option for the treatment of serious infections caused by these important pathogens. IMPORTANCE:More than 50 years of misuse and overuse of antibiotics has led to a plague of antibiotic resistance that threatens to reduce the efficacy of antimicrobial agents available for the treatment of infections due to resistant organisms. The main threat is nosocomial infections in which certain pathogens, notably the ESKAPE organisms, are essentially untreatable and contribute to increasing mortality and morbidity in surgical wards. The pipeline of novel antimicrobials in the pharmaceutical industry is essentially empty. Thus, there is a great need to seek for new sources for the treatment of recalcitrant infectious diseases. We describe experiments that demonstrate the efficacy of a "natural" medicine, Kisameet clay, against all of the ESKAPE strains. We suggest that this material is worthy of clinical investigation for the treatment of infections due to multidrug-resistant organisms.

| S-EPMC4742703 | biostudies-literature

Potent antibiotic design via guided search from antibacterial activity evaluations.

Project description:MotivationThe emergence of drug-resistant bacteria makes the discovery of new antibiotics an urgent issue, but finding new molecules with the desired antibacterial activity is an extremely difficult task. To address this challenge, we established a framework, MDAGS (Molecular Design via Attribute-Guided Search), to optimize and generate potent antibiotic molecules.ResultsBy designing the antibacterial activity latent space and guiding the optimization of functional compounds based on this space, the model MDAGS can generate novel compounds with desirable antibacterial activity without the need for extensive expensive and time-consuming evaluations. Compared with existing antibiotics, candidate antibacterial compounds generated by MDAGS always possessed significantly better antibacterial activity and ensured high similarity. Furthermore, although without explicit constraints on similarity to known antibiotics, these candidate antibacterial compounds all exhibited the highest structural similarity to antibiotics of expected function in the DrugBank database query. Overall, our approach provides a viable solution to the problem of bacterial drug resistance.Availability and implementationCode of the model and datasets can be downloaded from GitHub (https://github.com/LiangYu-Xidian/MDAGS).Supplementary informationSupplementary data are available at Bioinformatics online.

| S-EPMC9897189 | biostudies-literature

Dimeric 3,5-Bis(benzylidene)-4-piperidones: Tumor-Selective Cytotoxicity and Structure-Activity Relationships.

Project description:Background: The objective of this study is to find novel antineoplastic agents that display greater toxicity to malignant cells than to neoplasms. In addition, the mechanisms of action of representative compounds are sought. This report describes the cytotoxicity of a number of dimers of 3,5-bis(benzylidene)-4-piperidones against human malignant cells (promyelocytic leukemia HL-60 and squamous cell carcinoma HSC-2, HSC-3, and HSC-4). Methods: Tumor specificity was evaluated by the selectivity index (SI), that is the ratio of the mean CC50 for human non-malignant oral cells (gingival fibroblasts, pulp cells, periodontal ligament fibroblasts) to that for malignant cells. Results: The compounds were highly toxic to human malignant cells. On the other hand, these molecules were less toxic to human non-malignant cells. In particular, a potent lead molecule, 3b, was identified. A QSAR study revealed that the placement of electron-releasing and hydrophilic substituents into the aryl rings led to increases in cytotoxic potencies. The modes of action of a lead compound discovered in this study designated 3b were the activation of caspases-3 and -7, as well as causing PARP1 cleavage and G2 arrest, followed by sub-G1 accumulation in the cell cycle. This compound also depolarized the mitochondrial membrane and generated reactive oxygen species in human colon carcinoma HCT116 cells. In conclusion, this study has revealed that, in general, the compounds described in this report are tumor-selective cytotoxins.

| S-EPMC10821124 | biostudies-literature

Lipidated cyclic ?-AApeptides display both antimicrobial and anti-inflammatory activity.

Project description:Antimicrobial peptides (AMPs) are host-defense agents capable of both bacterial membrane disruption and immunomodulation. However, the development of natural AMPs as potential therapeutics is hampered by their moderate activity and susceptibility to protease degradation. Herein we report lipidated cyclic ?-AApeptides that have potent antibacterial activity against clinically relevant Gram-positive and Gram-negative bacteria, many of which are resistant to conventional antibiotics. We show that lipidated cyclic ?-AApeptides mimic the bactericidal mechanism of AMPs by disrupting bacterial membranes. Interestingly, they also harness the immune response and inhibit lipopolysaccharide (LPS) activated Toll-like receptor 4 (TLR4) signaling, suggesting that lipidated cyclic ?-AApeptides have dual roles as novel antimicrobial and anti-inflammatory agents.

| S-EPMC3947011 | biostudies-literature

Biotin analogues with antibacterial activity are potent inhibitors of biotin protein ligase.

Project description:There is a desperate need to develop new antibiotic agents to combat the rise of drug-resistant bacteria, such as clinically important Staphylococcus aureus. The essential multifunctional enzyme, biotin protein ligase (BPL), is one potential drug target for new antibiotics. We report the synthesis and characterization of a series of biotin analogues with activity against BPLs from S. aureus, Escherichia coli, and Homo sapiens. Two potent inhibitors with K i < 100 nM were identified with antibacterial activity against a panel of clinical isolates of S. aureus (MIC 2-16 ?g/mL). Compounds with high ligand efficiency and >20-fold selectivity between the isozymes were identified and characterized. The antibacterial mode of action was shown to be via inhibition of BPL. The bimolecular interactions between the BPL and the inhibitors were defined by surface plasmon resonance studies and X-ray crystallography. These findings pave the way for second-generation inhibitors and antibiotics with greater potency and selectivity.

| S-EPMC4025796 | biostudies-other

Bis-isatin derivatives: design, synthesis, and biological activity evaluation as potent dimeric DJ-1 inhibitors.

Project description:The PARK7 gene (encode DJ-1 protein) was first discovered as an oncogene and later found to be a causative gene for autosomal recessive early onset Parkinson's disease. DJ-1 has been proposed as a potential therapeutic anticancer target due to its pivotal role in tumorigenesis and cancer progression. Based on the homodimer structure of DJ-1, a series of bis-isatin derivatives with different length linkers were designed, synthesized, and evaluated as dimeric inhibitors targeting DJ-1 homodimer. Among them, DM10 with alkylene chain of C10 displayed the most potent inhibitory activity against DJ-1 deglycase. We further demonstrated that DM10 bound covalently to the homodimer of DJ-1. In human cancer cell lines H1299, MDA-MB-231, BEL7402, and 786-O, DM10 (2.5-20 μM) inhibited the cell growth in a concentration-dependent manner showing better anticancer effects compared with the positive control drug STK793590. In nude mice bearing H1299 cell xenograft, intratumor injection of DM10 (15 mg/kg) produced significantly potent tumor growth inhibition when compared with that caused by STK793590 (30 mg/kg). Moreover, we found that DM10 could significantly enhance N-(4-hydroxyphenyl)retinamide-based apoptosis and erastin-based ferroptosis in H1299 cells. In conclusion, DM10 is identified as a potent inhibitor targeting DJ-1 homodimer with the potential as sensitizing agent for other anticancer drugs, which might provide synergistical therapeutic option for cancer treatment.

| S-EPMC8209122 | biostudies-literature

Potent Broad-Spectrum Antibacterial Activity of Amphiphilic Peptides against Multidrug-Resistant Bacteria.

Project description:The emergence and prevalence of multidrug-resistant (MDR) bacteria particularly Gram-negative bacteria presents a global crisis for human health. Colistin and tigecycline were recognized as the last resort of defenses against MDR Gram-negative pathogens. However, the emergence and prevalence of MCR or Tet(X)-mediated acquired drug resistance drastically impaired their clinical efficacy. It has been suggested that antimicrobial peptides might act a crucial role in combating antibiotic resistant bacteria owing to their multiple modes of action and characteristics that are not prone to developing drug resistance. Herein, we report a safe and stable tryptophan-rich amphiphilic peptide termed WRK-12 with broad-spectrum antibacterial activity against various MDR bacteria, including MRSA, colistin and tigecycline-resistant Escherichia coli. Mechanistical studies showed that WRK-12 killed resistant E. coli through permeabilizing the bacterial membrane, dissipating membrane potential and triggering the production of reactive oxygen species (ROS). Meanwhile, WRK-12 significantly inhibited the formation of an E. coli biofilm in a dose-dependent manner. These findings revealed that amphiphilic peptide WRK-12 is a promising drug candidate in the fight against MDR bacteria.

| S-EPMC7564829 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data