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Deciphering the role of intramolecular networking in cholic acid-peptide conjugates (caps) at lipopolysaccharide surface in combating gram-negative bacterial infections

Yadav, Kavita and Kumar, Sandeep (2019) Deciphering the role of intramolecular networking in cholic acid-peptide conjugates (caps) at lipopolysaccharide surface in combating gram-negative bacterial infections. Journal of Medicinal Chemistry, 62 (4). pp. 1875-1886. ISSN 0022-2623

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Abstract

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. MD simulations and structural analysis revealed that 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 antimicrobial nature of compounds, and analysis presented here may serve as a general principle for design of future antimicrobials.

Item Type: Article
Subjects: Research > Research Center - Health Sciences
Depositing User: KMC Library
Date Deposited: 01 Apr 2019 03:57
Last Modified: 01 Apr 2019 03:57
URI: http://eprints.manipal.edu/id/eprint/153549

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