Cholic Acid-Based Antimicrobial Peptide Mimics as Antibacterial Agents

International Journal of Molecular Sciences

Naresh Kumar¹  David StC. Black¹  Tsz Tin Yu¹  Jie Wu¹  Md. Musfizur Hassan¹  Rajesh Kuppusamy¹  Amani Alghalayini²  Charles G. Cranfield²  Mark D. P. Willcox³ 

[1] School of Chemistry, The University of New South Wales, Sydney, NSW 2052, Australia;School of Life Sciences, University of Technology Sydney, P.O. Box 123, Ultimo, NSW 2007, Australia;School of Optometry and Vision Science, University of New South Wales, Sydney, NSW 2052, Australia;

关键词: cholic acid;    antimicrobial peptide;    peptidomimetics;    antibacterial;    membrane disruption;   

DOI  :  10.3390/ijms23094623

来源: DOAJ

【 摘 要 】

There is a significant and urgent need for the development of novel antibacterial agents to tackle the increasing incidence of antibiotic resistance. Cholic acid-based small molecular antimicrobial peptide mimics are reported as potential new leads to treat bacterial infection. Here, we describe the design, synthesis and biological evaluation of cholic acid-based small molecular antimicrobial peptide mimics. The synthesis of cholic acid analogues involves the attachment of a hydrophobic moiety at the carboxyl terminal of the cholic acid scaffold, followed by the installation of one to three amino acid residues on the hydroxyl groups present on the cholic acid scaffold. Structure–activity relationship studies suggest that the tryptophan moiety is important for high antibacterial activity. Moreover, a minimum of +2 charge is also important for antimicrobial activity. In particular, analogues containing lysine-like residues showed the highest antibacterial potency against Gram-positive S. aureus. All di-substituted analogues possess high antimicrobial activity against both Gram-positive S. aureus as well as Gram-negative E. coli and P. aeruginosa. Analogues 17c and 17d with a combination of these features were found to be the most potent in this study. These compounds were able to depolarise the bacterial membrane, suggesting that they are potential antimicrobial pore forming agents.

【 授权许可】

Unknown