Cholic Acid-Based Antimicrobial Peptide Mimics as Antibacterial Agents

• Published in: International journal of molecular sciences 2022-04, Vol.23 (9), p.4623
• Main Authors: Wu, Jie, Yu, Tsz Tin, Kuppusamy, Rajesh, Hassan, Md Musfizur, Alghalayini, Amani, Cranfield, Charles G, Willcox, Mark D P, Black, David StC, Kumar, Naresh
• Format: Article
• Language: English
• Subjects: Acid resistance; Amino acids; Anti-Bacterial Agents - chemistry; Anti-Infective Agents - pharmacology; antibacterial; Antibacterial activity; Antibacterial agents; Antibiotic resistance; Antibiotics; Antimicrobial activity; Antimicrobial agents; antimicrobial peptide; Antimicrobial Peptides; Bacteria; Bacterial infections; Cholic acid; Cholic Acid - pharmacology; Clinical trials; Drug resistance; Escherichia coli; Hydrochloric acid; Hydrophobicity; Hydroxyl groups; Lysine; membrane disruption; Microbial Sensitivity Tests; Peptides; peptidomimetics; Permeability; Pore formation; Residues; Scaffolds; Staphylococcus aureus; Staphylococcus infections; Structure-Activity Relationship; Tryptophan
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23094623

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 . All di-substituted analogues possess high antimicrobial activity against both Gram-positive as well as Gram-negative and . Analogues and 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.