Helical Antimicrobial Sulfono- {gamma} -AApeptides

Journal Article · Thu Jun 11 00:00:00 EDT 2015 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.5b00537· OSTI ID:1239549

Li, Yaqiong; Wu, Haifan; Teng, Peng; Bai, Ge; Lin, Xiaoyang; Zuo, Xiaobing; Cao, Chuanhai; Cai, Jianfeng

Host-defense peptides (HDPs) such as magainin 2 have emerged as potential therapeutic agents combating antibiotic resistance. Inspired by their structures and mechanism of action, herein we report the fi rst example of antimicrobial helical sulfono- γ - AApeptide foldamers. The lead molecule displays broad-spectrum and potent antimicrobial activity against multi-drug-resistant Gram- positive and Gram-negative bacterial pathogens. Time-kill studies and fl uorescence microscopy suggest that sulfono- γ -AApeptides eradicate bacteria by taking a mode of action analogous to that of HDPs. Clear structure - function relationships exist in the studied sequences. Longer sequences, presumably adopting more-de fi ned helical structures, are more potent than shorter ones. Interestingly, the sequence with less helical propensity in solution could be more selective than the stronger helix-forming sequences. Moreover, this class of antimicrobial agents are resistant to proteolytic degradation. These results may lead to the development of a new class of antimicrobial foldamers combating emerging antibiotic-resistant pathogens.

• Research Organization: Argonne National Lab. (ANL), Argonne, IL (United States)
• Sponsoring Organization: USDOE Office of Science - Office of Basic Energy Sciences - Scientific User Facilities Division
• DOE Contract Number: AC02-06CH11357
• OSTI ID: 1239549
• Journal Information: Journal of Medicinal Chemistry, Vol. 58, Issue 11; ISSN 0022-2623
• Publisher: American Chemical Society (ACS)
• Country of Publication: United States
• Language: English