Inhibitors of Protein-Protein Interactions to Disrupt Bacterial Iron Homeostasis

Case ID:

2019-016

BACKGROUND

The emergence of antibiotic resistant bacteria, and a marked decrease in the development of new antibiotics threaten to severely undermine many of the advances in modern medicine. Most antibiotics target a limited number of crucial biological processes, including DNA replication, protein translation, and cell wall biosynthesis. Thus, there is an urgent need to discover and validate novel biological targets in bacteria. In this context: iron is essential for bacteria due to its involvement in multiple metabolic processes. Pathogenic bacteria must obtain iron from the host, but humans maintain extremely low concentrations of free iron, which are additionally reduced during infections

SUMMARY OF TECHNOLOGY

Researchers at OSU and University of Kansas have developed an invention to disrupt iron homeostasis in bacteria. These small molecules inhibit interaction between bacterioferritin (BfrB) and ferredoxin (Bfd) proteins. This inhibition causes irreversible accumulations of Fe³⁺ in BfrB, resulting in cytosolic iron deficiency. A major benefit of disrupting this system is that BfrB-Bfd are only found in bacteria, making this system theoretically unable to damage eukaryotic cells. Test results confirm validity of Bfd binding site inhibition of the BfrB molecule in vitro as well as in Pseudomonas aeruginosa, inhibiting bacterial growth in iron-limiting conditions. Additionally, evidence shows these molecules are capable of potentiating the activity of existing antibiotics in the laboratory.