SsrA-based design of BacPROTACs for β-lactamase degradation in Gram-negative bacteria

Qichang Nie; Jessie Wing-Yin Wu; Kun Zhang; Shu Ling Lin; Carmen Oi Kwan Law; Ying Ying Zhang; Xuehan Wang; Yanjuan Gu; Zhong-Ping Yao; Wing-Tak Wong; Terrence Chi-Kong Lau

doi:10.1039/D5CC02015H

SsrA-based design of BacPROTACs for β-lactamase degradation in Gram-negative bacteria†

Qichang Nie,

^ab Jessie Wing-Yin Wu,

^cd Kun Zhang,^e Shu Ling Lin,^a Carmen Oi Kwan Law,^a Ying Ying Zhang,^a Xuehan Wang,^f Yanjuan Gu,

^f Zhong-Ping Yao,

^cd Wing-Tak Wong^f and Terrence Chi-Kong Lau

*^a

Author affiliations

* Corresponding authors

^a Department of Biomedical Sciences, and Tung Biomedical Sciences Centre, College of Biomedicine, City University of Hong Kong, Kowloon, Hong Kong SAR, China
E-mail: chiklau@cityu.edu.hk

^b , Department of Oncology, The First Hospital of Hebei Medical University, Shijiazhuang, China

^c Department of Applied Biology and Chemical Technology, Research Institute for Future Food, and Research Centre for Chinese Medicine Innovation, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, China

^d State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), and Shenzhen Key Laboratory of Food Biological Safety Control, Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China

^e Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China

^f Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China

Abstract

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 via ClpXP. This molecule demonstrated dual-binding specificity, dose-dependent proteolysis, and cefotaxime resensitization in resistant E. coli, enabling precision AMR targeting.

Chemical Communications

SsrA-based design of BacPROTACs for β-lactamase degradation in Gram-negative bacteria†

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SsrA-based design of BacPROTACs for β-lactamase degradation in Gram-negative bacteria

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