2. Academic Validation
  3. Naturally inspired chimeric quinolone derivatives to reverse bacterial drug resistance

Naturally inspired chimeric quinolone derivatives to reverse bacterial drug resistance

  • Eur J Med Chem. 2025 May 5:289:117496. doi: 10.1016/j.ejmech.2025.117496.
Qi Wen 1,  Yuhang He 2,  Jiaying Chi 3,  Luyao Wang 4,  Yixuan Ren 2,  Xiaoke Niu 4,  Yanqing Yang 5,  Kang Chen 1,  Qi Zhu 1,  Juncheng Lin 1,  Yanghui Xiang 6,  Junqiu Xie 2,  Wenteng Chen 1,  Yongping Yu 1,  Baohong Wang 6,  Bo Wang 7,  Ying Zhang 8,  Chao Lu 9,  Kairong Wang 10,  Peng Teng 11,  Ruhong Zhou 12
Affiliations

Affiliations

  • 1 Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Rd, Hangzhou, 310058, Zhejiang, China.
  • 2 Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, West Donggang Road 199, Lanzhou, 730000, China.
  • 3 State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, College of Pharmacy, Jinan University, Guangzhou, 511436, China.
  • 4 School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
  • 5 Zhejiang Key Laboratory of Cell and Molecular Intelligent Design and Development, Institute of Quantitative Biology, College of Life Sciences, Zhejiang University, Hangzhou, 310058, China.
  • 6 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
  • 7 School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China. Electronic address: bwang@njucm.edu.cn.
  • 8 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China. Electronic address: yzhang207@zju.edu.cn.
  • 9 State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, College of Pharmacy, Jinan University, Guangzhou, 511436, China. Electronic address: chaolu@jnu.edu.cn.
  • 10 Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, West Donggang Road 199, Lanzhou, 730000, China. Electronic address: wangkr@lzu.edu.cn.
  • 11 Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Rd, Hangzhou, 310058, Zhejiang, China; National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, 310058, China. Electronic address: pengteng@zju.edu.cn.
  • 12 Zhejiang Key Laboratory of Cell and Molecular Intelligent Design and Development, Institute of Quantitative Biology, College of Life Sciences, Zhejiang University, Hangzhou, 310058, China; Shanghai Institute for Advanced Study, Zhejiang University, Shanghai, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China; Department of Chemistry, Columbia University, New York, NY, USA.
PMID: 40088661 DOI: 10.1016/j.ejmech.2025.117496
Abstract

Antimicrobial resistance poses an urgent threat to global health, underscoring the critical need for new Antibacterial drugs. Ciprofloxacin, a third-generation quinolone Antibiotic, is used to treat different types of Bacterial infections; however, it often results in the rapid emergence of resistance in clinical settings. Inspired by low susceptibility to antimicrobial resistance of natural antimicrobial peptides, we herein propose a host defense peptide-mimicking strategy for designing chimeric Quinolone derivatives which may reduce the likelihood of Antibacterial resistance. This strategy involves the incorporation of deliberately designed amphiphilic moieties into ciprofloxacin to mimic the structural characteristics and resistance-evading properties of host defense peptides. A resulting chimeric compound IPMCL-28b, carrying a rigid linker and three cationic Amino acids along with a lipophilic acyl n-decanoyl tail, exhibited potent activity against a panel of multidrug-resistant Bacterial strains by endowing the ciprofloxacin derivatives with additional ability to disrupt Bacterial cell membranes. Molecular dynamics simulations showed that IPMCL-28b demonstrates significantly stronger disruptive interactions with cell membranes than ciprofloxacin. This compound not only demonstrated high selectivity with low hemolysis side effect, but also significantly reduced the likelihood of resistance development compared with ciprofloxacin. Excitingly, IPMCL-28b demonstrated highly enhanced in vivo antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA) with a 99.99 % (4.4 log) reduction in skin Bacterial load after a single dose. These findings highlight the potential of host defense peptides-mimicking amphiphilic ciprofloxacin derivatives to reverse Antibiotic resistance and mitigate the development of antimicrobial resistance.

Keywords

Antimicrobial resistance; Chimeric quinolone antibiotic; Host defense peptide; In vivo antimicrobial activity; Membrane disruption; Reverse drug resistance.

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