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ACS Applied Materials & Interfaces Feb 2022The rapid accumulation of dead bacteria or protein on a bactericidal surface can reduce the effectiveness of the modified surface and alter its biocidal activity by...
The rapid accumulation of dead bacteria or protein on a bactericidal surface can reduce the effectiveness of the modified surface and alter its biocidal activity by shielding the surface biocide functional groups, promoting microbial attachment and subsequent biofilm formation. Thus, the alteration of biocidal activity due to biofilm formation can cause serious trouble including severe infection or implant or medical device failure leading to death. Therefore, developing a smart self-cleaning surface is of great interest. Ideally, such a surface can not only kill the attached microbials but also release the dead cells and foulants from the surface under a particular incitement on demand. In this project, a sugar-responsive self-cleaning coating has been developed by forming covalent boronic ester bonds between catechol groups from polydopamine and a benzoxaborole pendant from zwitterionic and cationic polymers. To incorporate antifouling properties and enhance the biocompatibility of the coating, bioinspired zwitterionic compound 2-methacryloyloxyethyl phosphorylcholine (MPC) was chosen and benzoxaborole pendant containing zwitterionic polymer poly(MPC--MAABO) (MAABO: 5-methacrylamido-1,2-benzoxaborole) was synthesized. Additionally to impart antibacterial properties to the surface, a quaternary ammonium containing cationic polymer poly(2-(methacryloyloxy)ethyl trimethylammonium (META)--MAABO)) was synthesized. These synthesized polymers were covalently grafted to a polydopamine (PDA) coated surface by forming a strong cyclic boronic ester complex with a catechol group of the PDA layer endowing the surface with bacteria contact-killing properties and capturing specific protein. After the addition of -diol containing competitive molecules, i.e., saccharides/sugars, this boronic ester complex with a catechol group of PDA was replaced and the attached polymer layer was cleaved from the surface, resulting in the release of both absorbed protein and live/killed bacteria electrostatically attached to the polymer layer. This dynamic self-cleaning surface can be a promising material for biomedical applications avoiding the gathering of dead cells and debris that are typically encountered on a traditional biocidal surface.
Topics: Anti-Bacterial Agents; Bacteria; Biofouling; Dopamine; Phosphorylcholine; Surface Properties
PubMed: 35144379
DOI: 10.1021/acsami.1c19337 -
PloS One 2024Herein we report the design and the synthesis of a library of new and more hydrophilic bisindole analogues based on our previously identified antileishmanial compound...
Herein we report the design and the synthesis of a library of new and more hydrophilic bisindole analogues based on our previously identified antileishmanial compound URB1483 that failed the preliminary in vivo test. The novel bisindoles were phenotypically screened for efficacy against Leishmania infantum promastigotes and simultaneously for toxicity on human macrophage-like THP-1 cells. Among the less toxic compounds, eight bisindoles showed IC50 below 10 μM. The most selective compound 1h (selectivity index = 10.1, comparable to miltefosine) and the most potent compound 2c (IC50 = 2.7 μM) were tested for their efficacy on L. infantum intracellular amastigotes. The compounds also demonstrated their efficacy in the in vitro infection model, showing IC50 of 11.1 and 6.8 μM for 1h and 2c, respectively. Moreover, 1h showed a better toxicity profile than the commercial drug miltefosine. For all these reasons, 1h could be a possible new starting point for hydrophilic antileishmanial agents with low cytotoxicity on human macrophage-like cells.
Topics: Leishmania infantum; Humans; Antiprotozoal Agents; THP-1 Cells; Indoles; Hydrophobic and Hydrophilic Interactions; Phosphorylcholine; Macrophages; Inhibitory Concentration 50
PubMed: 38870204
DOI: 10.1371/journal.pone.0301901 -
Expert Opinion on Drug Discovery Jun 2020Visceral leishmaniasis (VL) is a vector-borne disease caused by or . Closely related to poverty, VL is fatal and represents one of the main burdens on public health in... (Review)
Review
INTRODUCTION
Visceral leishmaniasis (VL) is a vector-borne disease caused by or . Closely related to poverty, VL is fatal and represents one of the main burdens on public health in developing countries. Treatment of VL relies exclusively on chemotherapy, a strategy still experiencing numerous limitations. Miltefosine (MF) has been used in the chemotherapy of VL in some endemic areas, and has been expanded to other regions, being considered crucial in eradication programs.
AREAS COVERED
This article reviews the most relevant preclinical and clinical aspects of MF, its mechanism of action and resistance to parasites, as well as its limitations. The authors also give their perspectives on the treatment of VL.
EXPERT OPINION
The discovery of MF represented an enormous advance in the chemotherapy of VL, since it was the first oral drug for this neglected disease. Beyond selection of resistant parasites due to drug pressure, several other factors can lead to treatment failure such as, for example, factors intrinsic to the host, parasite and the drug itself. Although its efficacy as a monotherapy has reduced over recent years, MF is still an important alternative in VL chemotherapy, especially when used in combination with other drugs.
Topics: Animals; Antiprotozoal Agents; Drug Development; Drug Discovery; Humans; Leishmania donovani; Leishmania infantum; Leishmaniasis, Visceral; Phosphorylcholine
PubMed: 32202449
DOI: 10.1080/17460441.2020.1743674 -
Acta Tropica May 2018Lesihmaniasis is one of the major neglected tropical disease caused by the parasite of the genus Leishmania. The disease has more than one clinical forms and the... (Review)
Review
Lesihmaniasis is one of the major neglected tropical disease caused by the parasite of the genus Leishmania. The disease has more than one clinical forms and the visceral form is considered fatal. With the lack of potential vaccine, chemotherapy is the major treatment source considered for the control of the disease in the infected people. Drugs including amphotericin B and miltefosine are widely used for the treatment, however, development of resistance by the parasite towards the administered drug and high-toxicity of the drug are of major concern. Hence, more attention has been shown on identifying new targets, effective inhibitors, and better drug delivery system against the disease. This review deals with recent studies on drug targets and exploring their essentiality for the survival of Leishmania. Further, new inhibitors for those targets, novel anti-leishmanial peptides and vaccines against leishmaniasis were discussed. We believe that this pool of information will ease the researchers to gain knowledge and help in choosing right targets and design of new inhibitors against Leishmaniasis.
Topics: Amphotericin B; Animals; Antiprotozoal Agents; Drug Resistance; Humans; Leishmaniasis; Phosphorylcholine
PubMed: 29452111
DOI: 10.1016/j.actatropica.2018.02.010 -
Journal of Materials Chemistry. B Jul 2022To further enhance the cancerous cellular uptakes and increase the drug release of the drug loaded micelles, herein, we fabricated a series of mixed micelles with...
To further enhance the cancerous cellular uptakes and increase the drug release of the drug loaded micelles, herein, we fabricated a series of mixed micelles with different mass ratios using two amphiphilic copolymers P(DMAEMA--MaPCL) and PCL-SS-PMPC. The mixed micelles showed a prolonged circulation time due to the zwitterionic shells in a physiological environment (pH 7.4). In addition, because of the protonation of tertiary amine groups in PDMAEMA and the breakage of the disulfide bond in PMPC-SS-PCL in a tumor microenvironment, the mixed micelles aggregated, which led to enhanced cancerous cellular penetration and increased DOX release. Moreover, cytotoxicity assay showed that the mixed micelles had good biocompatibility to L929, HeLa and MCF-7 cells, even at a concentration of up to 1 mg mL. Furthermore, enhanced antitumour activity and cellular uptake of HeLa and MCF-7 cells were detected after loading with DOX, which was determined by confocal laser scanning microscopy (CLSM) and flow cytometry (FC), especially for the DOX@MIX 3 micelles (20% mass ratio of the P(DMAEMA--MaPCL)). Therefore, the mixed strategy provides a simple and efficient ways to promote anticancer drug delivery.
Topics: Doxorubicin; Drug Delivery Systems; Drug Liberation; Humans; Micelles; Phosphorylcholine
PubMed: 35815797
DOI: 10.1039/d2tb01061e -
The Journal of Physical Chemistry. B Jun 2015Several membrane proteins and numerous membrane-active peptides have been studied in detergent micelles by solution NMR. However, the detailed structure of these...
Several membrane proteins and numerous membrane-active peptides have been studied in detergent micelles by solution NMR. However, the detailed structure of these complexes remains unknown. We propose a modeling approach that treats the protein and detergent in atomistic detail and the solvent implicitly. The model is based on previous work on dodecylphosphocholine micelles, adapted for use with the CHARMM36 force field and extended to sodium dodecyl sulfate micelles. Solvation parameters were slightly adjusted to reproduce experimental data on aggregation numbers and critical micelle concentrations. To test the approach, several membrane-active peptides and three β-barrel membrane proteins were subjected to molecular dynamics simulations in the presence of a large number of detergent molecules. Their experimentally determined secondary structure was maintained and the RMSD values were less than 2 Å. Deformations were commonly observed in the N or C termini. The atomistic view of the protein-micelle systems that this approach provides could be useful in interpreting biophysical experiments carried out in the presence of detergent.
Topics: Detergents; Micelles; Molecular Dynamics Simulation; Nuclear Magnetic Resonance, Biomolecular; Phosphorylcholine; Protein Multimerization; Protein Structure, Secondary; Proteins; Sodium Dodecyl Sulfate; Solvents; Water
PubMed: 26035001
DOI: 10.1021/acs.jpcb.5b00171 -
Journal of Dentistry Sep 2016We recently developed a new rechargeable composite with nanoparticles of amorphous calcium phosphate (NACP) having long-term calcium (Ca) and phosphate (P) ion release;...
OBJECTIVES
We recently developed a new rechargeable composite with nanoparticles of amorphous calcium phosphate (NACP) having long-term calcium (Ca) and phosphate (P) ion release; however, this composite was not antibacterial. The objectives of this study were to: (1) incorporate dimethylaminohexadecyl methacrylate (DMAHDM) and 2-methacryloyloxyethyl phosphorylcholine (MPC) into rechargeable NACP composite, and (2) investigate mechanical properties, protein adsorption and biofilm response of composite, and the pH of biofilm medium.
METHODS
MPC, DMAHDM and NACP were mixed into a resin of ethoxylated bisphenol A dimethacrylate (EBPADMA) and pyromellitic glycerol dimethacrylate (PMGDM). Protein adsorption was measured using a micro bicinchoninic acid method. A human saliva microcosm biofilm model was used to grow biofilms on composites. Colony-forming units (CFU), live/dead assay, metabolic activity, and biofilm culture medium pH were determined. The tests used n=6.
RESULTS
The composite with 3% MPC had protein adsorption an order of magnitude less than that of a commercial composite (p<0.05). Control composites were fully covered by live bacteria. Live bacteria were reduced via MPC; 3% MPC+3% DMAHDM had the least live bacteria (p<0.05). The composite with 3% MPC+3% DMAHDM inhibited biofilm growth and viability, reducing biofilm CFU by 3 log compared to commercial control composite (p<0.05), while having a flexural strength similar to that of the commercial composite (p>0.1). The composite containing 3% MPC+3% DMAHDM with biofilm culture maintained a pH above 6.5, while the commercial composite had a cariogenic pH of 4.2 in biofilm culture medium.
CONCLUSIONS
The new protein-repellent and antibacterial NACP rechargeable composite substantially reduced biofilm growth, yielding a much higher pH than a commercial composite.
CLINICAL SIGNIFICANCE
This novel bioactive nanocomposite is promising to protect tooth structures from biofilm acids and caries. The method of using NACP, MPC and DMAHDM may be applicable to other dental materials to reduce plaque buildup and secondary caries.
Topics: Anti-Bacterial Agents; Biofilms; Calcium Phosphates; Humans; Methacrylates; Nanocomposites; Phosphorylcholine
PubMed: 27327110
DOI: 10.1016/j.jdent.2016.06.003 -
Chemical Reviews Apr 2018Membrane proteins perform a host of vital cellular functions. Deciphering the molecular mechanisms whereby they fulfill these functions requires detailed biophysical and... (Review)
Review
Membrane proteins perform a host of vital cellular functions. Deciphering the molecular mechanisms whereby they fulfill these functions requires detailed biophysical and structural investigations. Detergents have proven pivotal to extract the protein from its native surroundings. Yet, they provide a milieu that departs significantly from that of the biological membrane, to the extent that the structure, the dynamics, and the interactions of membrane proteins in detergents may considerably vary, as compared to the native environment. Understanding the impact of detergents on membrane proteins is, therefore, crucial to assess the biological relevance of results obtained in detergents. Here, we review the strengths and weaknesses of alkyl phosphocholines (or foscholines), the most widely used detergent in solution-NMR studies of membrane proteins. While this class of detergents is often successful for membrane protein solubilization, a growing list of examples points to destabilizing and denaturing properties, in particular for α-helical membrane proteins. Our comprehensive analysis stresses the importance of stringent controls when working with this class of detergents and when analyzing the structure and dynamics of membrane proteins in alkyl phosphocholine detergents.
Topics: Animals; Biophysical Phenomena; Cell Membrane; Detergents; Humans; Hydrophobic and Hydrophilic Interactions; Kinetics; Magnetic Resonance Spectroscopy; Membrane Proteins; Micelles; Models, Molecular; Phosphorylcholine; Protein Conformation; Protein Folding; Protein Stability; Solubility
PubMed: 29488756
DOI: 10.1021/acs.chemrev.7b00570 -
Proteins Feb 2022Oleosin is a hydrophobic protein that punctuates the surface of plant seed lipid droplets, which are 20 nm-100 μm entities that serve as reservoirs for high-energy...
Oleosin is a hydrophobic protein that punctuates the surface of plant seed lipid droplets, which are 20 nm-100 μm entities that serve as reservoirs for high-energy metabolites. Oleosin is purported to stabilize lipid droplets, but its exact mechanism of stabilization has not been established. Probing the structure of oleosin directly in lipid droplets is challenging due to the size of lipid droplets and their high degree of light scattering. Therefore, a medium in which the native structure of oleosin is retained, but is also amenable to spectroscopic studies is needed. Here, we show, using a suite of biophysical techniques, that dodecylphosphocholine micelles appear to support the tertiary structure of the oleosin protein (i.e., hairpin conformation) and render the protein in an oligomeric state that is amenable to more sophisticated biophysical techniques such as NMR.
Topics: Hydrophobic and Hydrophilic Interactions; Lipid Droplets; Magnetic Resonance Spectroscopy; Micelles; Phosphorylcholine; Plant Proteins
PubMed: 34596903
DOI: 10.1002/prot.26252 -
Journal of Natural Products Oct 2020species including , , and are used in traditional Chinese medicine as "Qinjiao" for the treatment of rheumatism, hepatitis, and pain. Four antifungal...
species including , , and are used in traditional Chinese medicine as "Qinjiao" for the treatment of rheumatism, hepatitis, and pain. Four antifungal bisphosphocholines [irlbacholine () and three new analogues, gentianalines A-C (, , and )] were identified from by a bioassay-guided fractionation and structure elucidation approach. Subsequent chemical analysis of 56 "Qinjiao" samples (45 from , five from , three from , and three from ) showed that bisphosphocholines were present in all four species, with irlbacholine as the major compound ranging from 2.0 to 6.2 mg per gram of dried material. Irlbacholine exhibited potent in vitro antifungal activity against , , , and with minimum inhibitory concentration (MIC) values of 0.63, 1.25, 10.0, and 5.0 μg/mL, respectively. Identification of the bisphosphocholines, a rare class of antifungal natural products, in these medicinal plants provides scientific evidence to complement their medicinal use. The bisphosphocholines carrying a long aliphatic chain possess amphiphilic molecule-like properties with a tendency of retention in both normal and reversed-phase silica gel column chromatography and thereby may be neglected in natural products discovery. This report may stimulate interest in this class of compounds, which warrant the further study of other biological activities as well.
Topics: Antifungal Agents; Biological Assay; Fungi; Gentiana; Microbial Sensitivity Tests; Molecular Structure; Phosphorylcholine; Plant Extracts; Plant Roots; Plants, Medicinal; Structure-Activity Relationship
PubMed: 33052051
DOI: 10.1021/acs.jnatprod.0c00584