Unravelling the molecular mechanisms of Type VI secretion system Pore-Forming Toxins

Objetivo

The T6S-PoreMech project aims to transform our understanding of bacterial warfare by analysing the Type VI secretion system's (T6SS) Pore-Forming Toxins (PFTs). It tackles two vital knowledge gaps: the absence of a systematic functional map of PFT families and the complete lack of atomic structures for their active, membrane-inserted pore form, representing a structural black hole.

The project proposes a new paradigm, suggesting that PFTs facilitate not just killing but also efficient predatory foraging through a controlled slow-bleed of nutrients from target cells. This vision will be evaluated through three integrated pillars.

1. Functional lexicon: Systematically identifying and characterising T6SS PFTs to differentiate between killing and foraging functions.

2. Atomic blueprint: Capturing the atomic structures of active PFT pores using advanced cryo-EM, overcoming technical challenges with innovative megabody technology.

3. Toxin-Immunity co-evolution: Unravelling the enigmatic mechanisms of PFT neutralisation by analysing toxin-immunity complex structures.

By connecting atomic structure to cellular function and ecological strategies, T6S-PoreMech will offer a revolutionary, multiscale perspective on microbial competition and establish a rational foundation for developing new antimicrobial therapies.