Research


T
he Krachler lab focuses on how host-pathogen interaction and in particular bacterial adhesion triggers changes in host signalling pathways to favor infection. 

In addition, we are investigating the application of bacterial adhesins as tools in anti-adhesion therapy and as probes for host membrane structures.


Our work on anti-adhesion therapy of bacterial infections described in 60 seconds:

Development of a bacterial adhesin into a next generation antimicrobial agent

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 MAM7-mediated attachment by pre-incubation of host cells with MAM7-based inhibitors significantly delays the onset of hallmarks of infections, such as pathogen-mediated cytotoxicity or the development of other adhesive structures, such as actin pedestals. We are currently trying to develop more effective tools based on MAM7 that could one day be used to prevent or treat certain bacterial infections.



Biochemical and structural 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.



Our work is funded by EMBO the Royal Society , Wellcome Trust the BBSRC and the University of Birmingham Fellowship Scheme.