Targeting bacterial kinases as a strategy to counteract antibiotic resistance
Antibiotic resistance is rapidly emerging as one of the most critical health threats, with resistant microorganisms progressively diminishing the effectiveness of established antibiotics. As a result, the development of therapeutic approaches that effectively target resistant pathogens is of utmost importance. In this study, we developed inhibitors for APH(2")-IVa, a bacterial kinase conveying resistance to aminoglycoside antibiotics. Starting from a hit of a fragment-based screening, we explored the inhibitory motif by structure-based design, ultimately leading to a series of triazole analogues. Advanced analogues displayed promising ADME properties, emerging selectivity vs a panel of human kinases, permeability in both Gram-positive and Gram-negative bacteria, and a moderate antibiotic efficacy for clinical strains of P. aeruginosa. Taken together, our results suggest inhibition of bacterial kinases could be a promising option to reinstall the efficacy of aminoglycoside antibiotics.
Authors
- Stefan Knapp (ORCID: https://orcid.org/0000-0001-5995-6494)
- Julien Kowalewski (ORCID: https://orcid.org/0009-0005-4042-8145)
- Catherine Dunyach‐Remy (ORCID: https://orcid.org/0000-0001-6884-470X)
- Katharina Rox (ORCID: https://orcid.org/0000-0002-8020-1384)
- Jean‐François Guichou (ORCID: https://orcid.org/0000-0002-7699-3235)
- Felix Hausch (ORCID: https://orcid.org/0000-0002-3710-8838)
- Vanessa Buffa (ORCID: https://orcid.org/0000-0002-7440-6949)
- Corinne Lionne (ORCID: https://orcid.org/0000-0002-6348-5311)
- Andreas Krämer (ORCID: https://orcid.org/0000-0003-3294-2660)
- Robin C. E. Deutscher
- Mathilde Tomaszczyk (ORCID: https://orcid.org/0009-0009-2818-9638)
- Matijas Cica
- G.-M. Qi (ORCID: https://orcid.org/0009-0002-3253-7075)
- Marion Richardoz
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Structural Genomics Consortium (CA)
- Technische Universität Darmstadt (DE)
- Centre de Biologie Structurale (FR)
- German Center for Infection Research (DE)
- Helmholtz Centre for Infection Research (DE)
- Université de Nîmes (FR)
Publication Details
- Journal
- Communications Chemistry
- Published
- 2025-12-04
- DOI
- https://doi.org/10.1038/s42004-025-01794-7
- Citations
- 1
- Primary Topic
- Bacterial Genetics and Biotechnology
- Type
- article
- Field-Weighted Citation Impact
- 1.82
Funders
- Deutsches Zentrum für Infektionsforschung
- Agence Nationale de la Recherche
- Bundesministerium für Bildung und Forschung
- Mitacs
- Association Vaincre la Mucoviscidose
- French Infrastructure for Integrated Structural Biology