An iGEM-Research Project: transFERRITIN A Ferritin-Based Drug-Delivery-System to combat Antibiotic Resistance
We would like to explain to you quickly in a few short sentences who we are and what iGEM is. Stay with us to learn more about our exiting and innovative project idea.
The acronym iGEM stands for international Genetically Engineering Machine competition, an international research competition in the area of Synthetic Biology, in which hundreds of teams from all over the world participate and compete with their own self developed project ideas. However, there is real competition only at the final four days conference in Paris (Grand Jamboree, 02.-05.11.23), when all teams come together and present their results. Until then, the teams cooperate for a year and network in order to improve the scientific exchange. Apart from the research on the laptop and in the lab tasks like public relation, science communication, scientific exchange with experts, financing and sponsoring, web design and programming, project planning, modelling and many more are relevant. That is why our team is set up very interdisciplinary: We are 16 students of the University of Hamburg from different disciplines of the MIN-Faculty such as Molecular Life Sciences, Biology, Chemistry, Nanoscience and Molecular Plant Science. This interdisciplinarity ensures that everyone can introduce his or her individual strengths in order to cover as many parts of the project as possible. Our mentors are Prof. Dr. Michael Kolbe and Dr. Mirko Himmel. We do our lab work at the labs of the modern Research Institute CSSB at the Desy Campus.
If we have raised your interest with these descriptions, feel free to contact us at: igem.hamburg@gmail.com to become a part of the next project. Now let us talk about science for a while and get a few facts straight:
The World Health Organization (WHO) has been warning against a health crisis caused by bacterial resistances for years. Even today, infections with resistant germs are among the most common causes of death all over the world. Consequently, the antibiotic resistances who are responsible for this will come in focus of medicine and research. The project “transFERRITIN” of the iGEM-Team Hamburg 2023 examines an innovative possibility of a Drug-Delivery-Systems with synergistic antibacterial components to combat resistant germs.
Ferritin is a natural storage and transport protein in humans and normally works as part of the iron metabolism. We intend to approach this transport system with “transFERRITIN” and use the human Ferritin as a scaffold for the targeted penetration of resistant pathogens. We will construct a Drug-Delivery-System for the agent transport into bacteria on this basis.
Fig. 1: Ferritin-subunit (left), assembled Ferritin made up from 24 subunits into an empty Protein-”Container” (right).
We will encapsulate a combination of antibacterial components in this system which will have a synergistic effect and thus inhibit potential antibiotic resistances. It is our vision to reactivate antibiotics which have become ineffective because of bacterial resistances. Ferritin has proven itself to be a useful container as the (dis-)assibilation of its 24 subunits can easily be regulated by changing the pH-value.
Fig. 2: Assembling Ferritin-subunits at pH 7 / 8 and Disassembling due to changes in the pH-value.
A key element of our project is the specific introduction of the Ferritin-agent-complex in bacterial target organisms. In order to facilitate the entry, we will merge Cell-Penetrating-Peptides (CPPs) with the outer Ferritin-surface. Cell Penetrating Peptides are peptides made up from a few amino acids, which have shown in some studies that they can pass through cell membranes together with a Cargo. In our project, we will test three different CPPs in order to examine the entry into the bacteria-cell.
Fig. 3: Cell Penetrating Peptides (left), assembled Ferritin with one CPP each per Ferritin-subunit (right).
In order to be sure to be able to transport the Ferritin-agent-complex specifically into a chosen bacterial strain, we work at a possibility to increase the specificity of the complex. One option would be to module a sidechain of the Ferritin-subunit in such a way that a nanobody i. e. a smaller version of an antibody may connect specifically one ligand on the surface of the bacteria with its free end by using Click-Chemistry.
Fig. 4: Nanobody, which is able to connect to a Ferritin-subunit and to a target bivalently (left), der Ferritin-agent-complex equipped with the nanobodies for a higher specificity (right).
After the optimization of our transport system in the model organism Escherichia coli, we will test the complex with Pseudomonas aeruginosa for the implementation of our system into the real world. In our project, we will pay special attention to the der modularity of the transport-system. The transport-complex is made up from different components, which can all be exchanged like a Lego-kit in order to be able to use the complex for different bacteria strains. This modularity ensures a highly flexible transport system for different application purposes.
Fig. 5: The mind map shows all the different components of our transport system.
What is the advantage of the transport compared to the administration of the conventional medication? Good question! We set up the hypothesis that the agents will be more effective locally by the transport into the bacteria cell and may have the same effect in a lower concentration. Thus, we increase the efficiency and save resources. Furthermore, we hope that the targeted transport will enable us to bypass possible resistance mechanisms of the bacterias, which we will substantiate by using the synergistic antibacterial agents. These hypotheses have to be examined in our project with experiments and monitoring.
If you have any questions regarding the project, the competition or the participation in the next iGEM-project, feel free to contact us at: igem.hamburg"AT"gmail.com.
As soon as our website will be online by the middle of October, you will find all information on our research project at: https://2023.igem.wiki/hamburg/.
Further insights into our project can be found at our Instagram-channel: igem.hamburg 
(Authors: Lisa Siemers, Fanny Ott, Maren Hinz)
References:
(1) https://www.who.int/news-room/fact-sheets/detail/antibiotic-resistance
(2) https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02724-0/fulltext
(4) Lee, HM., Ren, J., Tran, K.M. et al. Identification of efficient prokaryotic cell-penetrating peptides with applications in bacterial biotechnology. Commun Biol 4, 205 (2021). https://doi.org/10.1038/s42003-021-01726-w
(5) Ma Y, Li R, Dong Y, You C, Huang S, Li X, Wang F, Zhang Y. tLyP-1 Peptide Functionalized Human H Chain Ferritin for Targeted Delivery of Paclitaxel. Int J Nanomedicine. 2021 Feb 4;16:789-802. doi: 10.2147/IJN.S289005. PMID: 33568906; PMCID: PMC7869709.
(6) Mei Y, Chen Y, Sivaccumar JP, An Z, Xia N, Luo W. Research progress and applications of nanobody in human infectious diseases. Front Pharmacol. 2022 Aug 12;13:963978. doi: 10.3389/fphar.2022.963978. PMID: 36034845; PMCID: PMC9411660.
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