Tandem Guest-Host-Receptor Recognitions Precisely Guide Ciprofloxacin to Eliminate Intracellular Staphylococcus aureus |
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| Authors: | Dr. Wenjun Zhan Lingling Xu Zhiyu Liu Xiaoyang Liu Dr. Ge Gao Tiantian Xia Xiaotong Cheng Dr. Xianbao Sun Prof. Dr. Fu-Gen Wu Prof. Dr. Qian Yu Prof. Dr. Gaolin Liang |
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| Affiliation: | 1. State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, 210096 Nanjing, China These authors contributed equally to this work.;2. State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, 210096 Nanjing, China;3. State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, 215123 Suzhou, China |
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| Abstract: | Staphylococcus aureus (S. aureus) is able to hide within host cells to escape immune clearance and antibiotic action, causing life-threatening infections. To boost the therapeutic efficacy of antibiotics, new intracellular delivery approaches are urgently needed. Herein, by rational design of an adamantane (Ada)-containing antibiotic-peptide precursor Ada-Gly-Tyr-Val-Ala-Asp-Cys(StBu)-Lys(Ciprofloxacin)-CBT ( Cip-CBT-Ada ), we propose a strategy of tandem guest-host-receptor recognitions to precisely guide ciprofloxacin to eliminate intracellular S. aureus. Via guest-host recognition, Cip-CBT-Ada is decorated with a β-cyclodextrin-heptamannoside ( CD-M ) derivative to yield Cip-CBT-Ada/CD-M , which is able to target mannose receptor-overexpressing macrophages via multivalent ligand-receptor recognition. After uptake, Cip-CBT-Ada/CD-M undergoes caspase-1 (an overexpressed enzyme during S. aureus infection)-initiated CBT-Cys click reaction to self-assemble into ciprofloxacin nanoparticle Nano-Cip . In vitro and in vivo experiments demonstrate that, compared with ciprofloxacin or Cip-CBT-Ada , Cip-CBT-Ada/CD-M shows superior intracellular bacteria elimination and inflammation alleviation efficiency in S. aureus-infected RAW264.7 cells and mouse infection models, respectively. This work provides a supramolecular platform of tandem guest-host-receptor recognitions to precisely guide antibiotics to eliminate intracellular S. aureus infection efficiently. |
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| Keywords: | Antimicrobials Caspase-1 Host-Guest Interaction Nanoparticle Self-Assembly |
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