The Krachler lab is part of the Synthetic Biology and Microbiology and Infection focus at the University of Birmingham.
We explore how host-pathogen interactions and in particular bacterial adhesion triggers changes in host signalling pathways to favor infection. We harness the strategies bacteria use to interact with the host to develop novel anti-virulence strategies.
Development of adhesion inhibitors to counteract bacterial infections
Pathogen attachment to host tissues is one of the initial and most crucial events during the establishment of bacterial infections. Thus, interference with this step is an efficient strategy to fight bacterial colonization, and one that is not prone to the development of bacterial resistance. Our recent work has identified one of the factors involved in initial binding of host cells by a wide range of Gram-negative pathogens, Multivalent Adhesion Molecule (MAM) 7. Interference with pathogen attachment by using MAM7-based adhesion inhibitors significantly delays the onset of hallmarks of infections, such as pathogen-mediated cytotoxicity and spread of infection in vivo. We are currently trying to develop more effective adhesion inhibitors that one day could be used to prevent or treat certain bacterial infections in patients.
Our work on anti-adhesion therapy of bacterial infections described in 60 seconds:
Structural and functional characterization of adhesin - host cell receptor complexes
The bacterial adhesin MAM7 contains seven mce (mammalian cell entry) repeat domains mediating a complex interaction with the host cell receptors fibronectin and phosphatidic acid. While the interaction of MAM with the lipid phosphatidic acid is of high affinity and a single mce domain is sufficient to mediate binding, fibronectin-binding is of low affinity and requires multiple mce domains. We are performing a detailed characterization of the interactions between mce domains and their receptors using both biochemical assays and structural biology approaches. The focus is on identifying key determinants of binding-affinity and -specificity with the aim to construct MAM7 derivatives with improved affinity and altered host-specificity for use as therapeutics and as probes for host membrane structures.