Researchers Engineer Cholic Acid-derived Amphiphiles as Potential Antimicrobials against Gram-negative Bacterial and Polymicrobial Infections

Group led by Dr. Avinash Bajaj synthesized twenty cholic acid-peptide conjugates and screened them for different gram-negative bacterial species. They showed that glycine-valine derived cholic acid amphiphile is effective and less haemolytic as compared to other amphiphiles. Various biophysical and biochemical assays validated the membrane-disrupting properties of the amphiphile. MD simulations deciphered that rigidity provided by intramolecular networking is responsible for its therapeutic effect. Authors then tested the antimicrobial activity of the amphiphiles in murine models.

Authors further screened these twenty Cholic acid-peptide conjugates against different gram-positive bacterial and fungal strains. CAP-3 having glycine-valine at 3, 7 and 12 positions displayed broad spectrum antimicrobial activity and found to be most potent compound against gram-positive bacterial and fungal strains. Biological studies depicted that CAP-3 effectively destroys inter-kingdom polymicrobial biofilms and animal studies validated that CAP-3 is highly effective against wound and catheter infection models in mice.

Articles

1. Yadav K, Kumar S, Mishra S, Asad M, Mitra M, Yavvari PS, Gupta S, Vedantham M, Ranga P, Komalla V, Pal S, Sharma P, Kapil A, Singh A, Singh N, Srivastava A, Thukral L and Bajaj A (2019)Deciphering the Role of Intramolecular Networking in Cholic Acid-Peptide Conjugates (CAPs) at Lipopolysaccharide Surface in Combating Gram-negative Bacterial Infections. Med. Chem. 62:1875-1886 | DOI: 10.1021/acs.jmedchem.8b01357 (Just Accepted Manuscript)
2. Gupta S, Thakur J, Pal S, Gupta R, Mishra D, Kumar S, Yadav K, Saini A, Yavvari P, Vedantham M, Singh A, Srivastava A, Prasad R and Bajaj A (2019) Cholic Acid-Peptide Conjugates (CAPs) as Potent Antimicrobials against Interkingdom Polymicrobial Biofilms. Antimicrobial Agents Chemotherapy | DOI: 10.1128/AAC.00520-19