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Harnessing advanced computational and synthetic biology to understand phage lysin complexity

Project description

Novel strategies against antibiotic-resistant bacteria

Antibiotic resistance remains a pressing global health concern, driving the search for innovative antibacterial alternatives. Lysins, enzymes produced by bacteriophages, have emerged as promising tools as they have the ability to break down bacterial cell walls and kill pathogenic bacteria. While initial research has demonstrated considerable potential, progress has been hampered by the limited understanding of how lysins work. With the support of the Marie Skłodowska-Curie Actions programme, the COMPLENDO project aims to investigate the structure, function, and diversity of lysins. Researchers will use advanced computational tools and innovative testing platforms to provide deeper understanding of lysins. Insights obtained from this work are expected to guide smarter drug development and support future treatments against resistant infections.

Objective

"(Endo)lysins are phage-encoded enzymes that degrade the peptidoglycan layer of bacterial cell walls, facilitating the release of viral progeny. Both wild-type and engineered lysins have shown promise as alternatives or complements to antibiotics, of importance in light of rising antimicrobial resistance. However, current lysin research and development (R&D) efforts remain largely empirical, needing resource-intensive screening processes that often yield limited generalizable insights. This challenge is further compounded by the recent failure of the first clinical trial intended as proof-of-concept for lysins as antimicrobials, alongside new findings that demonstrate an unexplored complexity of lysins.

This makes the case for an investment in fundamental research to address unresolved questions about lysin structure and function. Specifically, this project will explore two major issues related to lysins from the two major bacterial macrostructural paradigms, namely: (i) the specificity determinants of enzymatically active domains (EADs) in Gram-positive lysins and (ii) the role of cell wall binding domains (CBDs) and antimicrobial peptide-like elements (AMLEs) in Gram-negative lysins.
To achieve this, I will deploy, for the first time in the field, advanced computational methods to generate fully synthetic lysins that will serve as scaffolds for testing specificity determinants in EADs. In addition, I will develop an ""in virio"" testing platform (IVTP) in collaboration with a research network that this project will help establish. The IVTP will be central to the project, allowing for the evaluation of functional diversity within the context of the phage-host interaction, thus overcoming the applied bias in current lysin research.

Ultimately, this project will deepen our understanding of the newfound complexity of lysins and contribute to the rationalization and de-risking of R&D pipelines addressing one of the 21st century's major healthcare challenges."

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HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships

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Call for proposal

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(opens in new window) HORIZON-MSCA-2024-PF-01

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Coordinator

AGENCIA ESTATAL CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICAS
Net EU contribution

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€ 194 074,56
Address
CALLE SERRANO 117
28006 MADRID
Spain

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Comunidad de Madrid Comunidad de Madrid Madrid
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Research Organisations
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