De novo design of miniprotein inhibitors of bacterial adhesins
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. Here, the authors show that protein design is a generalizable strategy to generate new antimicrobials by neutralizing the function of bacterial adhesins to combat two causative agents of urinary tract infections, E. coli and A. baumannii.
Authors
- Pearl Magala (ORCID: https://orcid.org/0000-0001-5087-3473)
- Sarai Bardales
- Patrick W. Erickson (ORCID: https://orcid.org/0000-0002-4913-2317)
- Morgan R. Timm (ORCID: https://orcid.org/0000-0002-2947-9508)
- Asim K. Bera (ORCID: https://orcid.org/0000-0001-9473-2912)
- Pavel Aprikian (ORCID: https://orcid.org/0009-0006-2690-1212)
- Ali H. Ellebedy (ORCID: https://orcid.org/0000-0002-6129-2532)
- Kevin O. Tamadonfar (ORCID: https://orcid.org/0000-0002-6481-9993)
- Scott J. Hultgren (ORCID: https://orcid.org/0000-0001-8785-564X)
- Andrew C. Hunt (ORCID: https://orcid.org/0000-0001-9620-593X)
- Aaron J. Schmitz (ORCID: https://orcid.org/0000-0002-8077-6751)
- Jerome S. Pinkner (ORCID: https://orcid.org/0000-0002-7389-7440)
- Alex Kang (ORCID: https://orcid.org/0000-0001-5487-0499)
- Edward D. B. Lopatto (ORCID: https://orcid.org/0000-0002-6625-6143)
- David A. Baker (ORCID: https://orcid.org/0000-0001-7896-6217)
- Evgeni V. Sokurenko (ORCID: https://orcid.org/0000-0003-2806-4121)
- Rachel E. Klevit (ORCID: https://orcid.org/0000-0002-3476-969X)
- Karen Dodson (ORCID: https://orcid.org/0000-0001-7421-9660)
- Irina Basova
- Gianluca Interlandi (ORCID: https://orcid.org/0000-0001-5445-9587)
- Desmond White
- Emily Joyce (ORCID: https://orcid.org/0009-0007-3230-1341)
- Andyna Vernet (ORCID: https://orcid.org/0000-0003-3875-5903)
- Kelli L. Hvorecny (ORCID: https://orcid.org/0000-0002-4609-6170)
- Anna A. Manchenko (ORCID: https://orcid.org/0000-0001-5982-4504)
- Veronika L Tchesnokova (ORCID: https://orcid.org/0000-0002-4235-5796)
- Adam M. Chazin-Gray (ORCID: https://orcid.org/0009-0005-9310-1891)
- Denise A. Sanick (ORCID: https://orcid.org/0000-0001-6903-0273)
- Mark J. Cartwright
- Tuscan Rock Thompson (ORCID: https://orcid.org/0009-0003-1876-106X)
Institutions
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- University of Washington (US)
- Washington University in St. Louis (US)
- Wyss Institute for Biologically Inspired Engineering
Publication Details
- Journal
- Nature Communications
- Published
- 2026-10-09
- DOI
- https://doi.org/10.1038/s41467-026-78123-6
- Primary Topic
- Biochemical and Structural Characterization
- Type
- article
- Field-Weighted Citation Impact
- 0.00