Antimicrobial peptide resistance mechanisms in adherent-invasive Escherichia coli

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In order to adapt to their environment, bacteria must convert environmental signals into an appropriate response. Understanding both the signals involved and the mechanisms by which they are incorporated into an observed phenotype allows us to develop strategies to intervene in these critical processes. In this proposal, we describe a research program that will allow us to understand how diverse strains of host-adapted adherent-invasive E. coli (AIEC) are able to effectively colonize the host small intestine in spite of the production of antimicrobial proteins that generally prevent bacterial colonization at this site. This adaptation is a critical step in the evolutionary process for bacterial pathogens. In previous work, we have identified proteins (ArlA, ArlB and ArlC) from one such AIEC strain that provide high level resistance to this class of molecules, and we hypothesize that resistance to this class of molecules will be a general feature of AIEC strains, because these strains are routinely isolated from the small intestine of IBD patients. This novel hypothesis will be tested with three specific aims 1) determining the molecular mechanism of resistance mediated by the ArlABC proteins, 2) developing a screen to assess whether this is a general phenomenon by utilizing a collection of other clinical AIEC strains that we have collected, and 3) by determining the specific biological response of these highly resistant strains in the context of an animal model of disease. This program will be highly relevant to basic researchers with an interest in bacterial responses to environmental stresses, to those studying bacterial-host interactions as well as to researchers working on treatments for colitis in the pharmaceutical industry. The research will also benefit Canada by providing the opportunity to train highly qualified personnel with prospects of work in both public and private sectors, within research labs of academia and related industries. ***