Pseudomonas aeruginosa has been identified as one of the critical priority bacteria for development of new antibiotics. Bacterial iron homeostasis is recognized as a possible novel therapeutic approach for antibiotic development because iron is an essential nutrient for bacterial growth. Bacterioferritin (BfrB) is the main iron storage protein in P.aeruginosa. Mobilization of iron stored in BfrB requires binding by its cognate ferredoxin, Bfd. Knocking out the bfd gene causes irreversible accumulation of iron in BfrB, low iron levels in the cytosol and excess secretion of pyoverdine. The co-crystal structure of the BfrB:Bfd complex was used to guide a fragment-based structure-guided approach to identify fragments that are bound to BfrB at the Bfd-binding site. A small library of analogs was developed by synthetically growing the fragment hits discovered by STD NMR. Co-crystal structures of the analogs bound to BfrB confirmed binding at the Bfd-binding site on BfrB. Investigations to be described in the poster allowed us to determine that these analogs can permeate the P. aeruginosa cell membrane, inhibit the mobilization of iron from BfrB, initiate an iron starvation response, and impair bacterial growth.

Small molecule inhibitors of the BfrB:Bfd interaction affect Pseudomonas aeruginosa growth by dysregulating iron homeostasis

2019 Fall National Meeting

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