Project

Back to overview

Bioinorganic Chemistry of Silver: Biomineralization, Silver Resistance, Antimicrobial Activity and more

Applicant Fromm Katharina M.
Number 178827
Funding scheme Project funding (Div. I-III)
Research institution Département de Chimie Université de Fribourg
Institution of higher education University of Fribourg - FR
Main discipline Inorganic Chemistry
Start/End 01.05.2018 - 30.11.2022
Approved amount 1'233'221.00
Show all

All Disciplines (2)

Discipline
Inorganic Chemistry
Biochemistry

Keywords (7)

silver; silver efflux pump; biomineralization; silver resistance; Antimicrobial activity; peptides; electron transfer

Lay Summary (German)

Lead
Silber - und wie es Bakterien tötet
Lay summary
Von Silber weiss man schon seit Jahrtausenden, dass es gesundheitsförderlich ist - allein schon, dass man eine Silbermünze in einen Brunnen wirft, um sich Glück und Gesundheit zu wünschen. Heute weiss man, dass Silber antimikrobiell wirkt und Bakterien abtöten kann - man weiss aber nicht genau, wie das auf molekularer Ebene passiert. Zudem gibt es auch Silber-resistente Bakterien, die gelernt haben, mit Silber in der Umwelt umzugehen. Wir möchten in diesem Projekt neue Silber-Verbindungen herstellen, die auch gegen resistente Bakterien wirken.
Zu diesem Zweck untersuchen wir auch die Resistenzmechanismen von Bakterien gegenüber Silber. Ein solcher Mechanismus findet sich in machen Bakterien, die gezielt Silberionen aus ihrem Inneren nach aussen pumpen können. Man nennt dies eine sogenannte Silber-Efflux-Pumpe. Diese besteht aus verschiedenen Molekülen, die man zwar identifiziert hat, von denen man aber die Rolle nicht genau kennt. Diese Rolle wollen wir genau untersuchen, denn wenn wir verstehen, wie genau die Pumpe funktioniert, kann man die Pumpe auch "austricksen". Im ersten Teil wollen wir also den Mechanismus der Pumpe genau verstehen und womöglich auch beeinflussen lernen.
Ein zweiter Resistenzmechanismus liegt darin, dass manche Bakterien Silberionen ausserhalb ihrer Zelle "unlöslich" machen, indem sie die Silberionen zu Silber-Nanopartikeln umwandelt. Dazu müssen Elektronen aus der Bakterienzelle nach aussen transportiert und auf die Silberionen übertragen werden. Wie genau das passiert, ist nicht bekannt und nur sehr schwierig zu untersuchen. Wir haben hier eine Methode entwickelt, wie man diesen Elektronentransport verfolgen kann. Wenn wir verstehen, wie dieser Transport funktioniert, kann man ihn auch beeinflussen.
Im Idealfall lernen wir also, wie Bakterien mit dem Silber umgehen, wie es wirkt und wie man die resistenten Bakterien dennoch abtöten kann.
Direct link to Lay Summary Last update: 04.04.2018

Lay Summary (English)

Lead
Silver - knowing how it kills bacteria
Lay summary
Silver is long known for having beneficial effects on health. Just imagine the tradition of throwing a silver coin into a well, wishing good health. Today, we know that silver can be antimicrobial while being non-toxic for humans, but the details of how silver acts is not known to the molecular level.
We want to learn more about the exact mechanism of action of silver in order to better design silver-containing drugs, and to combat even resistant bacteria. Bacterial resistance against silver can occur for example by pumping the silver out of the bacterial cell, using what is called a silver efflux pump. We study this pump to learn in detail its functioning. Knowing itsfunction means that we will also be able to block this efflux pump andhence trick out one kind of silver resistance mechanism. So, we will investigate how the molecules that build the efflux pump can bind silver ions, and how these are then transported out of the bacterial cell. If we understand how this works, we can develop for instance drugs that are able to block the silver pump, so that the silver ions cannot be transported out of the cell. If they stay inside the bacteria, they will end up killing the bacterium.
A second mechanism of bacterial resistance is the precipitation of silver outside of the bacterial cell. Soluble silver ions are thus transformed into less soluble metallic silver particles. Not much is known on how bacteria can transform silver ions to silver nanoparticles. This means that bacteria need to produce electrons, which are dumped onto the silver ions to obtain silver atoms. These electrons are produced inside of the bacterial cell and have to be transported through the bacterial cell membrane to the outside, where the metal ions "attack". This transport process is difficult to observe, but if we can learn how this occurs, we will be able to inhibit this mechanism. We have thus developed a method on how to "see" bacteria producing and transporting electrons. Our observations will help us to combat the resistance mechanism.
Ideally, we will understand these mechanisms by which bacteria deal with silver ions and develop compounds that allow to kill resistant bacteria. 

Direct link to Lay Summary Last update: 04.04.2018

Responsible applicant and co-applicants

Employees

Project partner

Publications

Publication
Multifunctional Anthracene-Based Ni-MOF with Encapsulated Fullerenes: Polarized Fluorescence Emission and Selective Separation of C 70 from C 60
Vasylevskyi Serhii I., Raffy Guillaume, Salentinig Stefan, Del Guerzo André, Fromm Katharina M., Bassani Dario M. (2022), Multifunctional Anthracene-Based Ni-MOF with Encapsulated Fullerenes: Polarized Fluorescence Emission and Selective Separation of C 70 from C 60, in ACS Applied Materials & Interfaces, 14(1), 1397-1403.
Memorial Issue Dedicated to Dr. Howard D. Flack: The Man behind the Flack Parameter
Housecroft Catherine E., Fromm Katharina M. (2021), Memorial Issue Dedicated to Dr. Howard D. Flack: The Man behind the Flack Parameter, in Chemistry, 3(3), 818-820.
NMR reveals the interplay between SilE and SilB model peptides in the context of silver resistance
Babel Lucille, Nguyen Minh-Ha, Mittelheisser Cédric, Martin Marie, Fromm Katharina M., Walker Olivier, Hologne Maggy (2021), NMR reveals the interplay between SilE and SilB model peptides in the context of silver resistance, in Chemical Communications, 57(70), 8726-8729.
General Chemistry: Large Classes, Mixed Public, Three Languages (A Personal Experience)
Fromm Katharina M. (2021), General Chemistry: Large Classes, Mixed Public, Three Languages (A Personal Experience), in CHIMIA International Journal for Chemistry, 75(1), 39-44.
New Antimicrobial Strategies Based on Metal Complexes
Claudel Mickaël, Schwarte Justine V., Fromm Katharina M. (2020), New Antimicrobial Strategies Based on Metal Complexes, in Chemistry, 2(4), 849-899.
Handling (Nano)Silver as Antimicrobial Agent: Therapeutic Window, Dissolution Dynamics, Detection Methods and Molecular Interactions
Abram Sarah‐Luise, Fromm Katharina M. (2020), Handling (Nano)Silver as Antimicrobial Agent: Therapeutic Window, Dissolution Dynamics, Detection Methods and Molecular Interactions, in Chemistry – A European Journal, 26(48), 10948-10971.
Kinetics and Mechanism of Mineral Respiration: How Iron Hemes Synchronize Electron Transfer Rates
Chabert Valentin, Babel Lucille, Füeg Michael P., Karamash Maksym, Madivoli Edwin S., Herault Nelly, Dantas Joana M., Salgueiro Carlos A., Giese Bernd, Fromm Katharina M. (2020), Kinetics and Mechanism of Mineral Respiration: How Iron Hemes Synchronize Electron Transfer Rates, in Angewandte Chemie International Edition, 59(30), 12331-12336.
Metal Nanoparticle–Microbe Interactions: Synthesis and Antimicrobial Effects
Khan Mujeebur R., Fromm Katharina M., Rizvi Tanveer F., Giese Bernd, Ahamad Faheem, Turner Raymond J., Füeg Michael, Marsili Enrico (2020), Metal Nanoparticle–Microbe Interactions: Synthesis and Antimicrobial Effects, in Particle & Particle Systems Characterization, 37(5), 1900419-1900419.
Chemistry of alkaline earth metals: It is not all ionic and definitely not boring!
Fromm Katharina M. (2020), Chemistry of alkaline earth metals: It is not all ionic and definitely not boring!, in Coordination Chemistry Reviews, 408, 213193-213193.
Appropriate Buffers for Studying the Bioinorganic Chemistry of Silver(I)
Babel Lucille, Bonnet-Gómez Soledad, Fromm Katharina (2020), Appropriate Buffers for Studying the Bioinorganic Chemistry of Silver(I), in Chemistry, 2(1), 193-202.
Silver-Containing Titanium Dioxide Nanocapsules for Combating Multidrug-Resistant Bacteria
Hérault Nelly, Wagner Julia, Abram Sarah-Luise, Widmer Jérôme, Horvath Lenke, Vanhecke Dimitri, Bourquin Carole, Fromm Katharina M (2020), Silver-Containing Titanium Dioxide Nanocapsules for Combating Multidrug-Resistant Bacteria, in International Journal of Nanomedicine, Volume 15, 1267-1281.
Different coordination abilities of 1,7- and 4,7-phenanthroline in the reactions with copper(II) salts: Structural characterization and biological evaluation of the reaction products
Stevanović Nevena Lj., Andrejević Tina P., Crochet Aurélien, Ilic-Tomic Tatjana, Drašković Nenad S., Nikodinovic-Runic Jasmina, Fromm Katharina M., Djuran Miloš I., Glišić Biljana Đ. (2019), Different coordination abilities of 1,7- and 4,7-phenanthroline in the reactions with copper(II) salts: Structural characterization and biological evaluation of the reaction products, in Polyhedron, 173, 114112-114112.
Silver(I) complexes with 4,7-phenanthroline efficient in rescuing the zebrafish embryos of lethal Candida albicans infection
Pavic Aleksandar, Savić Nada D., Glišić Biljana Đ., Crochet Aurélien, Vojnovic Sandra, Kurutos Atanas, Stanković Dalibor M., Fromm Katharina M., Nikodinovic-Runic Jasmina, Djuran Miloš I. (2019), Silver(I) complexes with 4,7-phenanthroline efficient in rescuing the zebrafish embryos of lethal Candida albicans infection, in Journal of Inorganic Biochemistry, 195, 149-163.
Synthesis and structural analysis of polynuclear silver(I) complexes with 4,7-phenanthroline
Stanojevic Ivana, Savic Nada, Crochet Aurélien, Fromm Katharina, Djuran Milos, Glisic Biljana (2019), Synthesis and structural analysis of polynuclear silver(I) complexes with 4,7-phenanthroline, in Journal of the Serbian Chemical Society, 84(7), 689-699.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
SCS Fall Meeting 2021 Poster Amino Acid Influence on Ag+ Binding Sites in Model Peptides Inspired by the Silver Resistance Protein SilE 10.09.2021 online, Switzerland Simond Lucille; Fromm Katharina M.; Walker Olivier; Hologne Maggy; Marquenet Florian;
SCS Fall Meeting 2021 Poster Modelling the active site of New-Delhi metallo-β-lactamase-1 10.09.2021 Online, Switzerland Fromm Katharina M.; Schwarté Justine;
Annual Meeting of the Swiss Society for Crystallography Poster Photo E/Z equilibrium of an alkene bond in pyrenes with stilbene-like motif 02.09.2021 Fribourg, Switzerland Fromm Katharina M.; Schwarté Justine;
72nd Annual Meeting of the International Society of Electrochemistry Talk given at a conference Extracellular electron transfer in Geobacter sulfurreducens: On Rates and Mechanism 29.08.2021 Jeju Island / online, Korean Republic (South Korea) Karamash Maksym; Fromm Katharina M.; Salgueiro Carlos;
Metalloagents in antimicrobial resistance Talk given at a conference Silver - with the licence to kill 14.01.2021 Hongkong / Fribourg / online, Hongkong Schwarté Justine; Salgueiro Carlos; Marquenet Florian; Walker Olivier; Karamash Maksym; Hologne Maggy; Fromm Katharina M.;


Self-organised

Title Date Place
Summer Academy of the Swiss Study Foundation: "Research, Ethics and Innovation" 04.09.2021 Magliaso, Switzerland
Annual Meeting of the Swiss Society for Crystallography 02.09.2021 Fribourg, Switzerland
Metalloagents in antimicrobial resistance 14.01.2021 Fribourg / Hong Kong / online, Switzerland
ChemMetBio2020 17.01.2020 Fribourg, Switzerland

Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Basic Skills Labs Workshop 01.12.2021 Fribourg, Switzerland Fromm Katharina M.; Schwarté Justine;
Futurs en tous genres Workshop 11.11.2021 Fribourg, Switzerland Fromm Katharina M.; Marquenet Florian;
Webinar Swiss Plastics Cluster : solutions bactéricides/antimicrobiennes pour les plastiques Talk 23.09.2021 Fribourg / online, Switzerland Schwarté Justine; Marquenet Florian; Fromm Katharina M.;
Master Work Workshop 01.09.2021 Fribourg, Switzerland Marquenet Florian; Fromm Katharina M.;
72nd Annual Meeting of the International Society of Electrochemistry Talk 29.08.2021 Jeju Island / online, Korean Republic (South Korea) Karamash Maksym; Fromm Katharina M.;
100 hours Master stage Workshop 01.06.2021 Fribourg, Switzerland Marquenet Florian; Fromm Katharina M.;
100 hours Master stage Workshop 01.02.2021 Fribourg, Switzerland Fromm Katharina M.; Marquenet Florian;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Explora: Chemistry Show German-speaking Switzerland 2021
Print (books, brochures, leaflets) Kolumne German-speaking Switzerland 2021
Media relations: radio, television SRF1: Persönlich SRF1 (Radio and TV) German-speaking Switzerland 2021

Awards

Title Year
European Chemistry Fellow 2019

Associated projects

Number Title Start Funding scheme
189931 “Experience Art & Science” - INTEGRATIVE HUMAN HEALTH DAY 01.10.2019 Agora
183293 Single Crystal Diffraction: Dual System 01.09.2019 R'EQUIP

Abstract

Silver is known for its antimicrobial properties since ancient times and was used in medical applications until the 1940s, when antibiotics were discovered. Forgotten until the upraise of antibiotic-resistant bacteria, it has since seen a revival in research. With the use of silver e.g. in wound dressings, silver-resistant bacteria emerged. Resistance may occur e.g. via expression of an efflux pump, while other bacteria are able to reduce ionic silver to silver nanoparticles (AgNPs).This research project copes in part A with the design of improved silver-based antimicrobial coordination compounds by combining the action of silver with another antibacterial metal ion, e.g. Cu2+ and Zn2+. To achieve this goal, we will use biocompatible ligands that possess two different binding sites. Dual action compounds are expected to be more efficient, also against Ag-resistant bacteria. Compounds will be characterized in solution and the solid state by NMR titration studies, single crystal structure analysis, UV-Vis, IR, elemental analysis and tested for antimicrobial and cytotoxic properties. To follow the compounds in cells, newly developed luminescent ligands allow monitoring via confocal fluorescence microscopy.It is at the same time important to understand the silver-resistance mechanisms of bacteria. In part B, we will continue to investigate the silver efflux pump Sil of some Gram-negative bacteria, in particular the unique periplasmic SilE protein whose role is still not fully understood (Ag+ binding with SilE and how Ag+ is exported). Another mechanism by which bacteria can reduce the toxicity of silver ions is by generating AgNPs outside of the cell (biomineralization), either at the membrane using cytochromes, or at the pili via electron transport through proteins (part C). For both the efflux pump and the biomineralization processes, we will start with model peptides to approach the full protein bottom-up. We have shown this technique successfully in a first study on short peptide excerpts from SilE, using NMR-titrations and competition fluorescence titrations for the determination of the Ag+ binding constants. Larger model peptides will lead us to a final understanding of the proteins themselves, hence of the mechanisms. Studies of the biomineralization at different concentrations will help to establish the electron transfer rates through the membrane to AgNPs. Understanding the antimicrobial and the silver resistance mechanisms is important for the future development of active compounds.
-