Combating Gram Negative AMR Pathogens by Understanding the Envelope-Breaching Mechanisms of Predatory Bacteria (360G-Wellcome-209437_A_17_Z)

We aim to determine the exact molecular mechanisms by which the bacterial predator Bdellovibrio invades Gram negative pathogen prey and whether components of its invasion machinery could be used in isolation as a new approach to the treatment of antimicrobially resistant (AMR) bacterial infections.Gram negative AMR pathogens are a major threat to healthcare. Their "extra" outer membrane is a barrier to effective drug delivery. We wish to learn from nature as Bdellovibrio is able to effortlessly pass through the envelope of pathogen, (but not host), cells and kill them from within. Whole-cell usage of live Bdellovibrio shows great therapeutic promise. However, a deeper understanding of the molecular mechanisms by which Bdellovibrio achieves invasion is essential to inform future therapeutic options. We will use our combined expertise (in microbial-genetics and microscopy, plus protein structure:function analysis of these unusual predators), and preparatory data including:- an RNAseq dataset from an invasion-stalled mutant -providing us with candidate proteins made during invasion; 3DSIM/fluorescence microscopy revealing a central pore, surrounding "collar" and a protein-tagged robust secretory vesicle at the predator-invasion site. Our end goal is to associate specific invasion protein function to these physical features of pore generation/entry, uncovering mechanisms used by nature to breach prey-envelopes.