Inhibition and Reversal of Microbial Attachment by an Antibody with Parasteric Activity against the FimH Adhesin of Uropathogenic .

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A common approach in the development of selective inhibitors for ligand-receptor interactions is targeting the receptor binding site with the expectation that inhibitors will sterically interfere with ligand binding and thus block receptor function via a competitive (orthosteric) mechanism. However, using monoclonal antibodies specific for the mannose-binding Escherichia coli adhesin, FimH, we demonstrate that the binding site epitopes allow for non-competitive inhibition that is more effective than orthosteric blocking. FimH, similar to other binding proteins, exhibits conformational flexibility of the ligand-binding pocket shifting between open (inactive) and tight (active) conformations, with relatively low- and high- affinity towards mannose. We show that an antibody that binds just one of the mannose-binding pocket loops prevents the shift from the inactive to the active conformation and hence blocks formation of high-affinity ligand-receptor complexes. This antibody type was more effective in inhibition of bacterial adhesion than anti-FimH antibodies competitively blocking mannose binding, and unlike the latter or a soluble ligand, showed the ability to detach an established bacterial biofilm from a ligand-coated surface. As the newly described antibody can bind the FimH pocket simultaneously with ligand, we refer to it as a parasteric (next-to-ligand) inhibitor that exhibits non-competitive inhibition from within the binding-pocket of the receptor.

Vyšlo v časopise: Inhibition and Reversal of Microbial Attachment by an Antibody with Parasteric Activity against the FimH Adhesin of Uropathogenic .. PLoS Pathog 11(5): e32767. doi:10.1371/journal.ppat.1004857
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004857

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