Direct Identification of a Siderophore Import Protein Using Synthetic Petrobactin Ligands

摘要

The increase of bacterial resistance against almost all clinically used antibiotics is one of the most pressing public health problems. While existing drugs are becoming less and less effective, only a few truly new antibiotics have found their way to clinical application in the last decades. The inhibition of novel biochemical pathways that are not addressed by currently used antibiotics offers a potentially successful strategy for the development of new drugs able to combat infections caused by resistant bacteria. In this context, the interference with the bacterial uptake of iron promoted by siderophores has become the focus of attention. Side-rophores are polar low-molecular-weight molecules with exceptionally high iron-binding affinities that are secreted and reimported by microorganisms through dedicated transport systems. In addition to blocking their biosynthesis, the inhibition of siderophore export and import proteins offers a promising approach for the development of new antibiotics, because siderophore-promoted iron uptake is essential for both the survival and virulence of pathogens.For many bacteria, however, there is only limited information available regarding the export and import systems involved. In addition, siderophore-binding proteins have been discovered so far only indirectly based on homology searches or growth phenotype analysis of mutants.