scholarly journals Design and synthesis of thiamine analogues to study their binding to the ECF transporter for thiamine in bacteria

MedChemComm ◽  
2016 ◽  
Vol 7 (5) ◽  
pp. 966-971 ◽  
Author(s):  
L. Monjas ◽  
L. J. Y. M. Swier ◽  
A. R. de Voogd ◽  
R. C. Oudshoorn ◽  
A. K. H. Hirsch ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Substrate Specificity ◽  
Small Molecules ◽  
Energy Coupling ◽  
Coupling Factor ◽  
Design And Synthesis ◽  
Further Development ◽  
Thiamine Analogues

This work presents new small molecules that bind to the protein ThiT, which confers substrate specificity to the Energy-Coupling Factor (ECF) transporter for thiamine. Further development of the molecules may lead to compounds with antimicrobial activity.

Discovery of Antibacterial Agents Inhibiting the Energy-Coupling Factor (ECF) Transporters by Structure-Based Virtual Screening

2020 ◽  
Author(s):  
Eleonora Diamanti ◽  
Inda Setyawati ◽  
Spyridon Bousis ◽  
leticia mojas ◽  
lotteke Swier ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Antibacterial Agents ◽  
Antimicrobial Agents ◽  
Energy Coupling ◽  
Coupling Factor ◽  
Design Synthesis ◽  
Screening Design ◽  
Starting Point ◽  
Wide Range ◽  
Vitamin Uptake

Here, we report on the virtual screening, design, synthesis and structure–activity relationships (SARs) of the first class of selective, antibacterial agents against the energy-coupling factor (ECF) transporters. The ECF transporters are a family of transmembrane proteins involved in the uptake of vitamins in a wide range of bacteria. Inhibition of the activity of these proteins could reduce the viability of pathogens that depend on vitamin uptake. Because of their central role in the metabolism of bacteria and their absence in humans, ECF transporters are novel potential antimicrobial targets to tackle infection. The hit compound’s metabolic and plasma stability, the potency (20, MIC Streptococcus pneumoniae = 2 µg/mL), the absence of cytotoxicity and a lack of resistance development under the conditions tested here suggest that this scaffold may represent a promising starting point for the development of novel antimicrobial agents with an unprecedented mechanism of action.<br>

Design and Synthesis of (E)-4-(2-Phenyl-2H-chromen-3-yl)but-3-en-2-ones and Evaluation of their In Vitro Antimicrobial Activity

2015 ◽  
Vol 12 (5) ◽  
pp. 352-358 ◽  
Author(s):  
Sabita Nayak ◽  
Subhendu Chakroborty ◽  
Sujitlal Bhakta ◽  
Pravati Panda ◽  
Seetaram Mohapatra ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Design And Synthesis

scholarly journals The design and synthesis of an antibacterial phenothiazine–siderophore conjugate

2018 ◽  
Vol 14 ◽  
pp. 2646-2650 ◽  
Author(s):  
Abed Tarapdar ◽  
James K S Norris ◽  
Oliver Sampson ◽  
Galina Mukamolova ◽  
James T Hodgkinson
Keyword(s):  
Small Molecules ◽  
Antibacterial Agents ◽  
Multidrug Resistant ◽  
Biological Evaluation ◽  
Amide Bond ◽  
Design And Synthesis ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Latent Tb ◽  
Covalently Linked

Siderophore–antibiotic conjugates consist of an antibiotic covalently linked by a tether to a siderophore. Such conjugates can demonstrate enhanced uptake and internalisation to the bacterial cell resulting in significantly reduced MIC values and extended spectrum of activity. Phenothiazines are a class of small molecules that have been identified as a potential treatment for multidrug resistant tuberculosis and latent TB. Herein we report the design and synthesis of the first phenothiazine–siderophore conjugate. A convergent synthetic route was developed whereby the functionalised phenothiazine component was prepared in four steps and the siderophore component also prepared in four steps. In M. smegmatis the functionalised phenothiazine demonstrated an equipotent MIC value in direct comparison to the parent phenothiazine from which it was derived. The final conjugate was synthesised by amide bond formation between the two components and global deprotection of the PMB protecting groups to unmask the catechol iron chelating groups of the siderophore. The synthesis is readily amenable to the preparation of analogues whereby the siderophore component of the conjugate can be modified. The route will be used to prepare a library of siderophore–phenothiazine conjugates for full biological evaluation of much needed new antibacterial agents.

scholarly journals Bacteriomimetic Liposomes Improve Antibiotic Activity of a Novel Energy-Coupling Factor Transporter Inhibitor

Pharmaceutics ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 4
Author(s):  
Menka Drost ◽  
Eleonora Diamanti ◽  
Kathrin Fuhrmann ◽  
Adriely Goes ◽  
Atanaz Shams ◽  
...  
Keyword(s):  
Model Organism ◽  
Energy Coupling ◽  
Coupling Factor ◽  
Free Drug ◽  
Drug Formulation ◽  
Phosphatidylcholine Liposomes ◽  
Loading Method ◽  
Fold Reduction ◽  
Hydrophobic Compound ◽  
Bacterial Growth Inhibition

Liposomes have been studied for decades as nanoparticulate drug delivery systems for cytostatics, and more recently, for antibiotics. Such nanoantibiotics show improved antibacterial efficacy compared to the free drug and can be effective despite bacterial recalcitrance. In this work, we present a loading method of bacteriomimetic liposomes for a novel, hydrophobic compound (HIPS5031) inhibiting energy-coupling factor transporters (ECF transporters), an underexplored antimicrobial target. The liposomes were composed of DOPG (18:1 (Δ9-cis) phosphatidylglycerol) and CL (cardiolipin), resembling the cell membrane of Gram-positive Staphylococcus aureus and Streptococcus pneumoniae, and enriched with cholesterol (Chol). The size and polydispersity of the DOPG/CL/± Chol liposomes remained stable over 8 weeks when stored at 4 °C. Loading of the ECF transporter inhibitor was achieved by thin film hydration and led to a high encapsulation efficiency of 33.19% ± 9.5% into the DOPG/CL/Chol liposomes compared to the phosphatidylcholine liposomes (DMPC/DPPC). Bacterial growth inhibition assays on the model organism Bacillus subtilis revealed liposomal HIPS5031 as superior to the free drug, showing a 3.5-fold reduction in CFU/mL at a concentration of 9.64 µM. Liposomal HIPS5031 was also shown to reduce B. subtilis biofilm. Our findings present an explorative basis for bacteriomimetic liposomes as a strategy against drug-resistant pathogens by surpassing the drug-formulation barriers of innovative, yet unfavorably hydrophobic, antibiotics.

scholarly journals A Systematic Review of Recently Reported Marine Derived Natural Product Kinase Inhibitors

Marine Drugs ◽  
2019 ◽  
Vol 17 (9) ◽  
pp. 493 ◽  
Author(s):  
Li ◽  
Wang ◽  
Zhang ◽  
Zhang ◽  
Sajeevan ◽  
...  
Keyword(s):  
Small Molecules ◽  
Natural Product ◽  
Drug Targets ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Disease States ◽  
Clinical Drugs ◽  
Kinase Inhibitory Activity ◽  
New Compounds ◽  
Further Development

Protein kinases are validated drug targets for a number of therapeutic areas, as kinase deregulation is known to play an essential role in many disease states. Many investigated protein kinase inhibitors are natural product small molecules or their derivatives. Many marine-derived natural products from various marine sources, such as bacteria and cyanobacteria, fungi, animals, algae, soft corals, sponges, etc. have been found to have potent kinase inhibitory activity, or desirable pharmacophores for further development. This review covers the new compounds reported from the beginning of 2014 through the middle of 2019 as having been isolated from marine organisms and having potential therapeutic applications due to kinase inhibitory and associated bioactivities. Moreover, some existing clinical drugs based on marine-derived natural product scaffolds are also discussed.

Design and Synthesis of Novel Benzopyran-2-one Derivatives of Expected Antimicrobial Activity through DNA Gyrase-B Inhibition

2008 ◽  
Vol 341 (11) ◽  
pp. 725-733 ◽  
Author(s):  
Ghaneya S. Hassan ◽  
Nahla A. Farag ◽  
Gehan H. Hegazy ◽  
Reem K. Arafa
Keyword(s):  
Antimicrobial Activity ◽  
Dna Gyrase ◽  
Design And Synthesis ◽  
Derivatives Of

scholarly journals Recent Advances in the Application of Metabolomics for Nutrition and Health

2019 ◽  
Vol 10 (1) ◽  
pp. 479-519 ◽  
Author(s):  
Diana González-Peña ◽  
Lorraine Brennan
Keyword(s):  
Small Molecules ◽  
Biological Samples ◽  
Large Scale ◽  
Dietary Assessment ◽  
Personalized Nutrition ◽  
Nutrition And Health ◽  
Successful Development ◽  
Nutrition Research ◽  
Epidemiology Studies ◽  
Further Development

Metabolomics is the study of small molecules called metabolites in biological samples. Application of metabolomics to nutrition research has expanded in recent years, with emerging literature supporting multiple applications. Key examples include applications of metabolomics in the identification and development of objective biomarkers of dietary intake, in developing personalized nutrition strategies, and in large-scale epidemiology studies to understand the link between diet and health. In this review, we provide an overview of the current applications and identify key challenges that need to be addressed for the further development of the field. Successful development of metabolomics for nutrition research has the potential to improve dietary assessment, help deliver personalized nutrition, and enhance our understanding of the link between diet and health.

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