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Can we make antibiotics work better?

This was the question that our team focused on this season. We began in winter looking for various topics and started with a strong interest in pharmaceuticals and drug chemistry. We started from the interest of some of our team members in the case of neutropenia and weak immune systems- ultimately this led us to antibiotics and the challenges with their use(in particular short half lifes in the blood). From there we began to ask if we could more broadly improve intravenous(IV) antibiotic delivery.

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We were intrigued by the projects of a past iGEM team and companies like Sartorius which designed albumin synthesis methods to deliver drugs via prebinding the drug directly to recombinant albumin before administration[1-2]. We found the work of iGEM team Tec-Chihuahua 2023 creating an albumin binding endolysin quite impressive [2]. After looking at both cases however we felt that we wanted our system to have a wider application that could be integrated into the existing medical system. We wanted to design an albumin binder like Tec-Chihuahua but by targeting intravenous delivery of antibiotics hope to secure a broader use case to help extend drug half life.

One of the most common classes of antibiotic drugs are cephalosporins.

Cephalosporins are beta lactam antibiotics with a conserved dihydrothiazine ring. Importantly, they are used to treat both specific infections as well as provide broad-spectrum extended coverage against gram-negative and gram-positive bacteria.

However, as these drugs are rapidly filtered by the kidneys, they often have dosing regimens that are difficult to follow in outpatient settings and place a large burden on inpatient staff.

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Extending the half-life of this class of drugs will lessen healthcare strain by creating friendlier dosing strategies while potentially influencing treatment by allowing certain cephalosporins to be prescribed in new settings.


Our solution:

Our project aims to extend the half-life of cephalosporins by using albumin, a blood plasma protein, for a piggyback ride. Using a previously characterized albumin-binding moiety, we will conjugate a Maleimide-PEG-OH linker to the moiety and a conserved cephalosporin carboxylic acid, creating a system to conjugate and extend the half-life of any cephalosporin. This linker is cleavable, thus allowing the antibiotic to be carried then released to carry out its function.

As a team we identified three main project goals to work towards:

  1. We planned to computationally design novel protein binders that could link with albumin effectively.
  2. Through pharmacokinetic modeling we hoped to determine the level of affinity between protein binder and albumin needed to significantly extend the half life of various drugs.
  3. Via our Human Practices and Modeling subteams we wanted to determine how our design could be integrated into the existing medical system. We also needed to know whether our approach could be made cost effective and safe for patients and providers.

Exploring Alternative Albumin Binders:

For different drug applications, there may be variations in the half-life of the drug desired and what properties are ideal for the albumin binder, such as binding affinity, temperature stability, pH-tolerance, and specific residue distribution. In addition to our approach of using an existing albumin binder to extend the half-life of antibodies, we will be exploring the use of deep learning-based tools like RFdiffusion, ProteinMPNN, and AlphaFold to design alternative structures and computationally observe and analyze the features that are predictive of real experimental results.

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Human serum albumin with three designed binders, visualized in ChimeraX.

References

[1.] “Recombinant Human Albumin | Sartorius,” Sartorius, 2024. https://www.sartorius.com/en/products/cell-culture-media/cell-culture-reagents-supplements/recombinant-human-albumin (accessed Sep. 28, 2024).
[2.] “Proof of concept | Tec-Chihuahua - iGEM 2023,” Igem.wiki, 2023. https://2023.igem.wiki/tec-chihuahua/proof (accessed Sep. 28, 2024).
[3.] V. B. Arumugham, M. Cascella, and R. Gujarathi, “Third Generation Cephalosporins,” PubMed, 2020. https://www.ncbi.nlm.nih.gov/books/NBK549881/
[4.]E. C. Meng et al., “UCSF ChimeraX: Tools for structure building and analysis,” Protein Sci., vol. 32, no. 11, p. e4792, 2023, doi: 10.1002/pro.4792.

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Washington iGEM

2024 Project MightyMoieties

uwigem@uw.edu

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