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  2. Deciphering the Role of Intramolecular Networking in Cholic Acid-Peptide Conjugates on the Lipopolysaccharide Surface in Combating Gram-Negative Bacterial Infections

Deciphering the Role of Intramolecular Networking in Cholic Acid-Peptide Conjugates on the Lipopolysaccharide Surface in Combating Gram-Negative Bacterial Infections

  • J Med Chem. 2019 Feb 28;62(4):1875-1886. doi: 10.1021/acs.jmedchem.8b01357.
Kavita Yadav 1 2 Sandeep Kumar 1 2 Deepakkumar Mishra 1 Mohammad Asad 1 Madhurima Mitra 1 Prabhu S Yavvari 3 Siddhi Gupta 1 Madhukar Vedantham 1 Pavit Ranga 1 Varsha Komalla 1 Sanjay Pal 1 4 Priyanka Sharma 5 Arti Kapil 5 Archana Singh 6 Nirpendra Singh 7 Aasheesh Srivastava 3 Lipi Thukral 6 Avinash Bajaj 1
Affiliations

Affiliations

  • 1 Laboratory of Nanotechnology and Chemical Biology , Regional Centre for Biotechnology , 3rd Milestone Faridabad-Gurgaon Expressway , NCR Biotech Science Cluster, Faridabad 121001 , Haryana , India.
  • 2 Manipal Academy of Higher Education , Manipal 576104 , Karnataka , India.
  • 3 Department of Chemistry , Indian Institute of Science Education and Research , Bhopal 462030 , Madhya Pradesh , India.
  • 4 Kalinga Institute of Industrial Technology , Bhubaneswar 751024 , Odisha , India.
  • 5 Department of Microbiology , All India Institute of Medical Sciences , Ansari Nagar , New Delhi 110029 , India.
  • 6 CSIR-Institute of Genomics and Integrative Biology , Mathura Road , New Delhi 110025 , India.
  • 7 Regional Centre for Biotechnology , 3rd Milestone Faridabad-Gurgaon Expressway , NCR Biotech Science Cluster, Faridabad 121001 , Haryana , India.
Abstract

The presence of lipopolysaccharide and emergence of drug resistance make the treatment of Gram-negative Bacterial infections highly challenging. Herein, we present the synthesis and Antibacterial activities of cholic acid-peptide conjugates (CAPs), demonstrating that valine-glycine dipeptide-derived CAP 3 is the most effective antimicrobial. Molecular dynamics simulations and structural analysis revealed that a precise intramolecular network of CAP 3 is maintained in the form of evolving edges, suggesting intramolecular connectivity. Further, we found high conformational rigidity in CAP 3 that confers maximum perturbations in Bacterial membranes relative to Other small molecules. Interestingly, CAP 3-coated catheters did not allow the formation of biofilms in mice, and treatment of wound infections with CAP 3 was able to clear the Bacterial infection. Our results demonstrate that molecular conformation and internal connectivity are critical parameters to describe the antimicrobial nature of compounds, and the analysis presented here may serve as a general principle for the design of future antimicrobials.

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