Year: 2025
Type: preprint
Abstract: The rise of multidrug-resistant bacterial infections necessitates the discovery of novel antimicrobial strategies. Here, we show that protein design provides a generalizable means of generating new antimicrobials by neutralizing the function of bacterial adhesins, which are virulence factors critical in host-pathogen interactions. We de novo designed high-affinity miniprotein binders to FimH and Abp chaperone usher pili adhesins from uropathogenic Escherichia coli and Acinetobacter baumannii , respectively, which are implicated in mediating both uncomplicated and catheter-associated urinary tract infections (UTI) responsible for significant morbidity worldwide. The designed antagonists have high specificity and stability, disrupt bacterial recognition of host receptors, block biofilm formation, and are effective in treating and preventing murine models of uncomplicated and catheter-associated UTIs in vivo .
Authors: Adam M. Chazin-Gray, Tuscan R. Thompson, Edward D. B. Lopatto, Pearl Magala, Patrick W. Erickson, Andrew C. Hunt, Anna Manchenko, Pavel Aprikian, Veronika Tchesnokova, Irina Basova, Denise A. Sanick, Kevin O. Tamadonfar, Morgan R. Timm, Jerome S. Pinkner, Karen W. Dodson, Alex Kang, Emily Joyce, Asim K. Bera, Aaron J. Schmitz, Ali H. Ellebedy, Kelli L. Hvorecny, Gianluca Interlandi, Mark J. Cartwright, Andyna Vernet, Sarai Bardales, Desmond White, Rachel E. Klevit, Evgeni V. Sokurenko, Scott J. Hultgren, David Baker
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: U.S. Department of Energy, National Institutes of Health, Office of Science, Advanced Research Projects Agency, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, Biological and Environmental Research, Argonne National Laboratory, Brookhaven National Laboratory
Awards: G1021286281, G102163711, G107546177, G1285306620, G1313983767, G1664757510, G171842289, Investigating Novel Methods to Combat Urinary Tract Infections, G1867732070, G2287611682, G241279073, G262962599, G2857925935, G3075337988, G3262563802, G3388457521, G357145406, G409777406, G4155925329, G4429385918, G498139845, G5535608740, G5607048534, G5765906131, Chaperone-Assisted Pili Assembly in Pathogenic E. Coli, G6476969910, Optimization of protective antibodies response against bacterial adhesins, G6848031779, G6918803902, G7103625430, G7463374569, G78868261, G8461821187, G8775485830, G9000051782, Center for Biomolecular Structure (CBMS), ALS Efficiently Networking Advanced Beam Line Experiments (ALS-ENABLE), Allosteric adhesins of enterobacterial pathogens, Innovative Strategies to Combat Antibiotic-resistant Infections, Novel therapeutics for treatment of catheter-associated UTI and depletion of the vaginal reservoir, NE-CAT: A Resource for Advanced Macromolecular Crystallography, Pathogenic Fiber Formation in Bacteria: Structural Basis, G969889393, G993149817
OpenAlex ID: W4413303057