SsrA-based design of BacPROTACs for β-lactamase degradation in Gram-negative bacteria
Antimicrobial resistance (AMR) challenges infection control amid limited antibiotic innovation. While bacterial proteolysis-targeting chimeras (BacPROTACs) degrade resistance factors in Gram-positive pathogens, their application in critical Gram-negative species remains unexplored. We engineered a Gram-negative-specific BacPROTAC, NacssrA-1, to degrade the β-lactamase CTX-M-14 <i>via</i> ClpXP. This molecule demonstrated dual-binding specificity, dose-dependent proteolysis, and cefotaxime resensitization in resistant <i>E. coli</i>, enabling precision AMR targeting.
Authors
- Terrence Chi‐Kong Lau (ORCID: https://orcid.org/0000-0002-7505-7306)
- Zhong‐Ping Yao (ORCID: https://orcid.org/0000-0003-3555-9632)
- Wing‐Tak Wong (ORCID: https://orcid.org/0000-0002-3453-1825)
- Jiannan Wu (ORCID: https://orcid.org/0000-0001-6018-4612)
- Xiutong Wang (ORCID: https://orcid.org/0000-0001-8389-2080)
- Shili Lin (ORCID: https://orcid.org/0000-0003-2467-4491)
- Ying Ying Zhang
- Kun Zhang (ORCID: https://orcid.org/0000-0002-6971-1164)
- Qichang Nie (ORCID: https://orcid.org/0000-0002-4176-8062)
- Yanjuan Gu (ORCID: https://orcid.org/0000-0003-2345-9060)
- Carmen Oi Kwan Law
Institutions
- Tung Wah College (HK)
- Hebei Medical University (CN)
- Hong Kong Polytechnic University (HK)
- Sun Yat-sen University (CN)
- City University of Hong Kong (HK)
- Fifth Affiliated Hospital of Sun Yat-sen University (CN)
- Chinese University of Hong Kong, Shenzhen (CN)
- First Affiliated Hospital of Hebei Medical University (CN)
Publication Details
- Journal
- Chemical Communications
- Published
- 2025-01-01
- DOI
- https://doi.org/10.1039/d5cc02015h
- Citations
- 3
- Primary Topic
- Peptidase Inhibition and Analysis
- Type
- article
- Field-Weighted Citation Impact
- 3.14
Funders
- City University of Hong Kong
- Research Grants Council, University Grants Committee
- Food and Health Bureau
- Basic and Applied Basic Research Foundation of Guangdong Province