The Krachler lab is part of the Synthetic Biology and Microbiology and Infection focus at the University of Birmingham.
We explore how information is exchanged at the bacteria-host interface, and how this impacts the balance between health and disease states. The main questions driving our work are: "How do bacteria perceive the host and react by switching on colonization or virulence mechanisms? And how, in turn, does the physicochemical process of bacterial adhesion affect the host in a way that facilitates colonization and infection?" While deepening our understanding of the basic biology of bacteria-host interactions, we concurrently work on translating our discoveries into clinically relevant applications, focusing on novel therapeutics to combat bacterial infections.
Development of adhesion inhibitors to combat drug-resistant 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 less prone to the development of drug 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-inspired biomimetic 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:
Emergence of resistance and suppression of drug-resistant populations during treatment
We closely work with Sara Jabbari's group at the University of Birmingham and clinical scientists at UT Southwestern Medical Center, to explore the emergence of resistance, both to antibiotics and anti-virulence drugs, during individual or combinatorial treatment with adhesion inhibitors (Ternent et al, 2015). We use clinical isolates as a basis to study the dynamics of mixed drug sensitive and resistant bacterial populations at infection sites with different spacial structures (such as burns or laceration wounds) and identify treatment scenarios (e.g., combination therapy, multi-target therapy, ) in which the emergence of drug resistant clones will be suppressed.
Structural and functional characterization of adhesin - host lipid 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 host membrane lipids. The seafood borne pathogen Vibrio parahaemolyticus expresses a MAM which binds host phosphatidic acids with high affinity and specificity. This interaction leads to lipid coalescence and downstream GTPase activation, which ultimately renders the host susceptible to invasive infection and septicemia (Lim et al, PLoS Pathog 2014). More recent data suggest that enteric pathogens and commensal strains differ in their host lipid binding specificity. We are now trying to answer how these dfferences in ligand binding specificity affect bacterial interactions with their host, host signaling processes and how this determines the fate of bacteria-host interactions and impacts the balance between intestinal health and disease states. We are performing a detailed characterization of the interactions between MAMs and their receptors using a multidisciplinary approach encompassing cellular microbiology, biochemistry and structural biology.