Bacterial Injection Machines within the Human Gut: Structure, Function and Potential as Novel Avenue in Precision Medicine to Battle Antimicrobial Resistance

Gut beneficial bacteria produce a newly discovered molecular syringe, so called Bacteroides injection system (BIS) and genes thereof were shown to be predominant in 99% of healthy human beings. Structure and function of these injection systems within the gut microbiome is to date unknown.

The proposed project will solve the BIS structure in various functional states (year 1–2) using cryo-electron microscopy (cryo-EM), supported by de novo structure prediction (AlphaFold2). We reveal the syringes’ molecular design and mechanistic function in native and non-native environment.

Furthermore, we will reveal the BIS target receptor (year 2–3) using receptor binding assays, surface plasmon resonance (SPR), mass spectrometry and microscopy revealing eukaryotic or bacterial cells as a target.

CRISPR gene edited Bacteroides strains (year ½–1.5) will be made to investigate the syringes’ importance in bacterial competition and potential to fight pathogens using in vitro and in vivo bacterial and mouse model systems, respectively.

BIS will be re-designed for treatment of infections and resistance (year 2–4) by modifying cargo and fiber legs using modelling and in vitro and in vivo transport and efficacy assays.

The proposed research package will present the first BIS structure, the effect and importance on gut microbiota and show its potential as targeted drug delivery tool and for microbiome editing to fight antimicrobial resistance.