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Elena Pascual García
MSc Biomedical Sciences / Leiden University, The Netherlands

PharMetrX Research+ Program
PhD student year: 2021

University of PhD: University of Potsdam
Supervisor: Prof. Wilhelm Huisinga
Co-Supervisor: Prof. Charlotte Kloft
Mentoring I-Partner: Boehringer Ingelheim

PhD Project

Model-based analysis of antibacterial combination therapies

Antimicrobial resistance is on the rise globally. Increased levels of resistance have been reported across bacterial strains and antibiotic compounds. Of special concern are multi-drug resistant infections that do not respond to last-resource antibiotics, leaving patients without available treatment options. Some predictions estimate that by 2050, 10 Million deaths per year will be attributed to bacterial resistance, making it a major threat to human health [1].

Tackling this issue by developing novel compounds has proved to be a difficult process: economic, regulatory and scientific bottlenecks significantly slow down the antibiotic pipeline, making evident the need for innovative ways of slowing the emergence and spread of resistance [2].

Antibiotic combination therapies are a promising approach to potentiate treatment and slow resistance evolution. However, mixing two compounds can also lead to a loss of effect or an increase in toxicity [3,4]. Key to predicting antibiotic efficacy and developing new therapeutic approaches is a thorough understanding of the relationship between drug susceptibility and bacterial physiology.

In my project, I focus on a mechanistic modelling approach that aims at making quantitative predictions of antibiotic effect on bacterial growth dynamics under different environmental conditions. I focus on ribosome-targeting antibiotics, which constitute more than half of drugs used to treat infections and are among the most successful antimicrobials.

Specifically, we model the uptake of antibiotics and their dynamic interplay with ribosomes within an established model of bacterial growth physiology [5].

 

[1] O’Neill, J. Tackling drug-resistant infections globally: final report and recommendations. (2016).

[2] Gupta, S. K. & Nayak, R. P. Dry antibiotic pipeline: Regulatory bottlenecks and regulatory reforms. Journal of Pharmacology & Pharmacotherapeutics 5, 4 (2014).

[3] Tyers, M. & Wright, G. D. Drug combinations: a strategy to extend the life of antibiotics in the 21st century. Nature Reviews Microbiology 2018 17:3 17, 141–155 (2019).

[4] Coates, A. R. M., Hu, Y., Holt, J. & Yeh, P. Antibiotic combination therapy against resistant bacterial infections: synergy, rejuvenation and resistance reduction. Expert review of anti-infective therapy 18, 5–15 (2020).

[5] Weiße, A. Y., Oyarzún, D. A., Danos, V. & Swain, P. S. Mechanistic links between cellular trade-offs, gene expression, and growth. Proceedings of the National Academy of Sciences of the United States of America 112, E1038–E1047 (2015).

 


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Publications

Please see the list of all publications and PhD theses.

Education

  • 08/2021: Entering PharMetrX

  • 09/2018–03/2021: M.Sc. Biomedical Sciences at Leiden University, The Netherlands
    - 7 months junior research project at Leiden University Medical Center (LUMC)
    - 9 months master thesis internship at Leiden Academic Centre for Drug Research (LACDR)

  • 9/2013–01/2018: B.Sc. Biomedical Sciences at Universitat Autonoma de Barcelona, Spain
    - Erasmus semester at Universita di Pisa, Italy