19
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      An Amphotericin B Derivative Equally Potent to Amphotericin B and with Increased Safety

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Amphotericin B is the most potent antimycotic known to date. However due to its large collateral toxicity, its use, although long standing, had been limited. Many attempts have been made to produce derivatives with reduced collateral damage. The molecular mechanism of polyene has also been closely studied for this purpose and understanding it would contribute to the development of safe derivatives. Our study examined polyene action, including chemical synthesis, electrophysiology, pharmacology, toxicology and molecular dynamics. The results were used to support a novel Amphotericin B derivative with increased selectivity: L-histidine methyl ester of Amphotericin B. We found that this derivative has the same form of action as Amphotericin B, i.e. pore formation in the cell membrane. Its reduced dimerization in solution, when compared to Amphotericin B, is at least partially responsible for its increased selectivity. Here we also present the results of preclinical tests, which show that the derivative is just as potent as Amphotericin B and has increased safety.

          Related collections

          Most cited references46

          • Record: found
          • Abstract: found
          • Article: not found

          Antifungal activity of the clove essential oil from Syzygium aromaticum on Candida, Aspergillus and dermatophyte species.

          The composition and antifungal activity of clove essential oil (EO), obtained from Syzygium aromaticum, were studied. Clove oil was obtained commercially and analysed by GC and GC-MS. The EO analysed showed a high content of eugenol (85.3 %). MICs, determined according to Clinical and Laboratory Standards Institute protocols, and minimum fungicidal concentration were used to evaluate the antifungal activity of the clove oil and its main component, eugenol, against Candida, Aspergillus and dermatophyte clinical and American Type Culture Collection strains. The EO and eugenol showed inhibitory activity against all the tested strains. To clarify its mechanism of action on yeasts and filamentous fungi, flow cytometric and inhibition of ergosterol synthesis studies were performed. Propidium iodide rapidly penetrated the majority of the yeast cells when the cells were treated with concentrations just over the MICs, meaning that the fungicidal effect resulted from an extensive lesion of the cell membrane. Clove oil and eugenol also caused a considerable reduction in the quantity of ergosterol, a specific fungal cell membrane component. Germ tube formation by Candida albicans was completely or almost completely inhibited by oil and eugenol concentrations below the MIC values. The present study indicates that clove oil and eugenol have considerable antifungal activity against clinically relevant fungi, including fluconazole-resistant strains, deserving further investigation for clinical application in the treatment of fungal infections.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Structural determinants of the supramolecular organization of G protein-coupled receptors in bilayers.

            The G protein-coupled receptor (GPCR) rhodopsin self-assembles into supramolecular structures in native bilayers, but the structural determinants of receptor oligomerization are not known. We carried out multiple self-assembly coarse-grained molecular dynamics (CGMD) simulations of model membranes containing up to 64 molecules of the visual receptor rhodopsin over time scales reaching 100 μs. The simulations show strong preferential interaction modes between receptors. Two primary modes of receptor-receptor interactions are consistent with umbrella sampling/potential of mean force (PMF) calculations as a function of the distance between a pair of receptors. The preferential interfaces, involving helices (H) 1/8, 4/5 and 5, present no energy barrier to forming a very stable receptor dimer. Most notably, the PMFs show that the preferred rhodopsin dimer exists in a tail-to-tail conformation, with the interface comprising transmembrane H1/H2 and amphipathic H8 at the extracellular and cytoplasmic surfaces, respectively. This dimer orientation is in line with earlier electron microscopy, X-ray, and cross-linking experiments of rhodopsin and other GPCRs. Less stable interfaces, involving H4 and H6, have a free energy barrier for desolvation (delipidation) of the interfaces and appear to be designed to stabilize "lubricated" (i.e., lipid-coated) dimers. The overall CGMD strategy used here is general and can be applied to study the homo- and heterodimerization of GPCRs and other transmembrane proteins. Systematic extension of the work will deepen our understanding of the forces involved in the membrane organization of integral membrane proteins.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              An improved united atom force field for simulation of mixed lipid bilayers.

              We introduce a new force field (43A1-S3) for simulation of membranes by the Gromacs simulation package. Construction of the force fields is by standard methods of electronic structure computations for bond parameters and charge distribution and specific volumes and heats of vaporization for small-molecule components of the larger lipid molecules for van der Waals parameters. Some parameters from the earlier 43A1 force field are found to be correct in the context of these calculations, while others are modified. The validity of the force fields is demonstrated by correct replication of X-ray form factors and NMR order parameters over a wide range of membrane compositions in semi-isotropic NTP 1 atm simulations. 43-A1-S3 compares favorably with other force fields used in conjunction with the Gromacs simulation package with respect to the breadth of phenomena that it accurately reproduces.
                Bookmark

                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                28 September 2016
                2016
                : 11
                : 9
                : e0162171
                Affiliations
                [1 ]Instituto de Ciencias Físicas, Universidad Nacional Autónoma de México, Apartado Postal 48-3, 62251, Cuernavaca, Morelos, México
                [2 ]Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, Col. Chamilpa Cuernavaca, Morelos, México
                [3 ]Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, Col. Chamilpa Cuernavaca, Morelos, México
                [4 ]Laboratorio Nacional de Genómica para la Biodiversidad, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Unidad Irapuato, km 9.6 Libramiento Norte, Carretera Irapuato-León, Irapuato, Guanajuato 36821, México
                [5 ]Departamento de Física, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Unidad Mérida. Km 6, Carretera Antigua a Progreso, Cordemex, 97310, Mérida, Yucatán, México
                [6 ]Groningen Biomolecular Sciences and Biotechnology Institute & Zernike Institute for Advanced Materials, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands
                [7 ]Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Batalla del 5 de Mayo y Fuerte de Loreto México DF, 09230, México City, México
                US Geological Survey, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: AA XP JRE IR MCT MFZ LRF IOB.

                • Formal analysis: AA JMFG DFR JGD FEJM ALB MLO RM SJM RMN XP JRL TMSA MCVG IR MCT MFZ LRF IOB.

                • Funding acquisition: MFZ LRF IOB.

                • Investigation: AA MEC JMFG DFR JGD FEJM ALB MLO RM SJM RMN JRL TMSA IR MCT MFZ LRF IOB.

                • Methodology: AdV JGD SJM RMN XP JRE IR MCT MFZ LRF IOB.

                • Project administration: MCVG IR MFZ LRF IOB.

                • Resources: IR MCT MFZ LRF IOB.

                • Software: AA AdV MEC JMFG JGD SJM XP IOB.

                • Supervision: MCVG IR MCT MFZ LRF IOB.

                • Validation: AdV JMFG DFR JGD FEJM ALB MLO RM SJM RMN XP JRL TMSA MCVG IR MFZ LRF IOB.

                • Visualization: AA JMFG JGD FEJM ALB MLO RM RMN TMSA IR MCT MFZ LRF IOB.

                • Writing – original draft: AA AdV JMFG DFR SJM RMN XP IR MCT MFZ LRF IOB.

                • Writing – review & editing: AA RMN IR MCT MFZ LRF IOB.

                [¤]

                Current address: Ciencias de la Computación. Centro de Investigación en Matemáticas, A. C., Guanajuato, México

                Article
                PONE-D-15-50088
                10.1371/journal.pone.0162171
                5040443
                27683101
                25d36c0a-bec9-40ea-bcb8-51f872698a19
                © 2016 Antillón et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 10 February 2016
                : 16 August 2016
                Page count
                Figures: 15, Tables: 11, Pages: 38
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100003141, Consejo Nacional de Ciencia y Tecnología;
                Award ID: 128575
                Award Recipient : Ivan Ortega-Blake
                Funded by: funder-id http://dx.doi.org/10.13039/501100006087, Dirección General Asuntos del Personal Académico, Universidad Nacional Autónoma de México;
                Award ID: IG100416
                Award Recipient : Ivan Ortega-Blake
                This study was supported by Consejo Nacional de Ciencia y Tecnología (grant number 128575) and Universidad Nacional Autónoma de México (PAPIIT grant number IG100416). http://www.conacyt.gob.mx/index.php/sni/convocatorias-conacyt/convocatorias-fondos-sectoriales-constituidos/convocatoria-sep-conacyt/investigacion-basica-sep/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Anatomy
                Renal System
                Kidneys
                Medicine and Health Sciences
                Anatomy
                Renal System
                Kidneys
                Physical Sciences
                Chemistry
                Chemical Properties
                Dimerization
                Physical Sciences
                Chemistry
                Physical Chemistry
                Chemical Properties
                Dimerization
                Medicine and Health Sciences
                Pharmacology
                Drugs
                Antimicrobials
                Antifungals
                Amphotericin
                Biology and Life Sciences
                Microbiology
                Microbial Control
                Antimicrobials
                Antifungals
                Amphotericin
                Biology and Life Sciences
                Mycology
                Antifungals
                Amphotericin
                Biology and Life Sciences
                Toxicology
                Toxicity
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Toxicology
                Toxicity
                Medicine and Health Sciences
                Urology
                Genitourinary Infections
                Candidiasis
                Medicine and Health Sciences
                Infectious Diseases
                Sexually Transmitted Diseases
                Candidiasis
                Biology and Life Sciences
                Organisms
                Fungi
                Yeast
                Candida
                Candida Albicans
                Biology and Life Sciences
                Microbiology
                Medical Microbiology
                Microbial Pathogens
                Fungal Pathogens
                Candida Albicans
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Pathogens
                Microbial Pathogens
                Fungal Pathogens
                Candida Albicans
                Biology and Life Sciences
                Mycology
                Fungal Pathogens
                Candida Albicans
                Research and Analysis Methods
                Model Organisms
                Yeast and Fungal Models
                Candida Albicans
                Physical sciences
                Chemistry
                Chemical physics
                Dimers (Chemical physics)
                Physical sciences
                Physics
                Chemical physics
                Dimers (Chemical physics)
                Physical Sciences
                Chemistry
                Chemical Compounds
                Organic Compounds
                Amides
                Physical Sciences
                Chemistry
                Organic Chemistry
                Organic Compounds
                Amides
                Custom metadata
                All relevant data are within the paper and its Supplementary Section.

                Uncategorized
                Uncategorized

                Comments

                Comment on this article