Small molecules for perturbing iron homeostasis in bacterial biofilms

Active Project Grant Awarded Last action

Award ID
R01AI169344
Recipient
Awarding agency
Obligated
$7,298,679

Award facts

Assistance listing
93.855 Allergy and Infectious Diseases Research
Completion date 95% complete
Place of performance
Baton Rouge, LA 70803, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Chronic wound care is especially complicated by the formation of bacterial biofilms, commonly by pseudomonas aeruginosa, acinetobacter baumannii and staphylococcus aureus. Biofilms are recalcitrant to antibiotic therapy, which is an important reason why chronic wound infections are so difficult to eradicate. There is a significant need to discover new strategies to combat biofilms. Bacterial iron homeostasis is a suitable novel target for developing anti-infectives because the host makes essential iron scarce to invading pathogens. Bacteria have evolved mechanisms to "steal" iron from their host, but these depend on well-regulated iron homeostasis. To disrupt bacterial iron homeostasis, we are targeting the iron storage protein bfrb and its physiological partner protein, BFD, which are unique to bacteria. Our work has shown that bfrb regulates cytosolic iron concentrations by (a) oxidizing FE2+ and storing up to ~3,000 FE3+ ions in its internal cavity, and (B) forming a complex with BFD to reduce FE3+ in the internal cavity of bfrb and release FE2+ to the cytosol for its incorporation in metabolism. Blocking the bfrb-BFD complex in P. Aeruginosa cells by deletion of the BFD gene perturbs iron homeostasis by triggering an irreversible accumulation of FE3+ in bfrb and simultaneous cytosolic iron depletion, which leads to impaired biofilm maintenance and biofilm cell death. Our work also led to the discovery of proof-of-concept inhibitors of the bfrb-BFD complex, which bind bfrb at the BFD binding site, inhibit iron mobilization, and elicit biofilm cell death. The objectives of this application are to improve the proof-of-concept molecules into lead molecules, evaluate their antibacterial and antibiofilm effectiveness, and evaluate their potential drug suitability. Our interdisciplinary team includes expertise in chemical and structural biology of bacterial iron homeostasis (RIVERA), organic synthesis and reaction mechanisms (BUNCE), pharmaceutical industry research and development of anti-infectives (REITZ), X-RAY crystallography in drug discovery (LOVELL), microbial genetics (CHANDLER), and animal model of infection (MORICI). The specific aims are: 1) evolve proof-of-concept analogs into potent inhibitors of the bfrb-BFD complex. This work will follow a systematic, iterative strategy of medicinal chemistry synthesis optimization that relies on crystal structures of inhibitor bound bfrb to design each new generation of inhibitors. 2) asses the antibacterial effectiveness of inhibitors of the bfrb-BFD complex and evaluate their potential drug suitability.

Transactions

Action Obligated Date
Amendment $736,587
Amendment $739,544
Amendment $73,498
Amendment $73,498
Amendment $661,489
Amendment $661,489
Amendment $661,489
Amendment $728,617
Amendment $728,617
Amendment $728,617
Amendment $728,617
Original award $776,617
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Subawards

Subrecipient Amount Awarded
Oklahoma State University Bacterioferritin (BfrB) is an iron storage protein that concentrates and stores Fe3+ and helps to maintain iron homeostasis in bacteria. The release of Fe2+… $588,960
Fox Chase Chemical Diversity Center Inc. Fox Chase Chemical Diversity Center, Inc. will prepare new analogs based on the work described in the grant application and a joint J. Am. Chem. Soc.… $655,112
University Of Kansas Center For Research Inc. Scott Lovell PhD, (SUBRECIPIENT Principal Investigator), Director of the University of Kansas Protein Structure Laboratory, will oversee all structural… $337,365
Fox Chase Chemical Diversity Center Inc. Fox Chase Chemical Diversity Center, Inc. will prepare new analogs based on the work described in the grant application and a joint J. Am. Chem. Soc.… $384,429
Oklahoma State University Bacterioferritin (BfrB) is an iron storage protein that concentrates and stores Fe3+ and helps to maintain iron homeostasis in bacteria. The release of Fe2+… $348,568
University Of Kansas Center For Research Inc. Scott Lovell PhD, (SUBRECIPIENT Principal Investigator), Director of the University of Kansas Protein Structure Laboratory, will oversee all structural… $199,665

Quick answers

Who received award R01AI169344?

R01AI169344 was awarded to Louisiana State University by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on February 15, 2022.

How much is award R01AI169344 worth?

$7,298,679 has been obligated on R01AI169344.

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