Discovery of quaternary ammonium compounds with broad antibacterial activity and efficacy in S. aureus infection model

  • Eur J Med Chem. 2025 Dec 20:305:118491. doi: 10.1016/j.ejmech.2025.118491.
Akash Shinde  1 ,  Deepanshi Saxena  2 ,  Rahul Maitra  2 ,  Swechchha Singh  3 ,  Abdul Akhir  2 ,  Shivani Maykalwar  1 ,  Kranthi Gupta  4 ,  B Angayarkanni  5 ,  Karnati Sai Pranathi  6 ,  Sunil Misra  7 ,  Vijayan N Azger Dusthackeer  5 ,  Jagadeesh Babu Nanubolu  8 ,  Sidharth Chopra  3 ,  Haridas B Rode  9
Affiliations
  • 1. Department of Natural Products and Medicinal Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500 007, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201 002, India.
  • 2. Department of Molecular Microbiology and Immunology, CSIR-Central Drug Research Institute, Sitapur Road, Jankipuram Extension, Lucknow, 226 031, Uttar Pradesh, India.
  • 3. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201 002, India; Department of Molecular Microbiology and Immunology, CSIR-Central Drug Research Institute, Sitapur Road, Jankipuram Extension, Lucknow, 226 031, Uttar Pradesh, India.
  • 4. Department of Natural Products and Medicinal Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500 007, India.
  • 5. Department of Bacteriology, National Institute for Research in Tuberculosis, Chennai, 600 031, India.
  • 6. Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500 007, India.
  • 7. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201 002, India; Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500 007, India.
  • 8. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201 002, India; Centre for X-ray Crystallography, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India.
  • 9. Department of Natural Products and Medicinal Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500 007, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201 002, India. Electronic address: [email protected].
PMID: 41500164 DOI: 10.1016/j.ejmech.2025.118491
Abstract

Antimicrobial resistance (AMR) has become a significant global health concern, contributing heavily to the morbidity and mortality associated with both hospital-acquired (nosocomial) and community-acquired infections. In this context, we investigated the Antibacterial potential of quinoline-based quaternary ammonium compounds (QACs) against Gram-positive bacteria, including multidrug-resistant (MDR) strains. Compound 20 was identified through a detail Structure-Activity-Relationship study and demonstrated strong Antibacterial potential with an MIC of 0.125 μg/mL against S. aureus. This compound is effective against clinical MDR-MRSA and VRSA. Of note, 20 effectively inhibited Bacterial growth in both planktonic and biofilm forms in a concentration-dependent manner. It's favorable toxicity profile (SI 72 w.r.t. CHO-K1 cells, HC50 of >100 μg/mL against human RBC) and prolonged post-antibiotic effect (PAE) compared to vancomycin highlights its potency as a safe therapeutic agent. Notably, the compound's in vitro efficacy was successfully translated in vivo, supporting its potential for development into a novel treatment for drug-resistant S. aureus infections, particularly for topical applications.

Keywords
Antibacterial agents; Biofilm inhibitors; Drug resistant S. aureus; Quaternary ammonium compounds; Quinolinium analogues.
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