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Rational Design of Dimeric Lysine N-Alkylamides as Potent and Broad-Spectrum Antibacterial Agents.

Rational Design of Dimeric Lysine N-Alkylamides as Potent and Broad-Spectrum Antibacterial Agents.

Authors :
Youhong Niu
Minghui Wang
Yafei Cao
Alekhya Nimmagadda
Jianxing Hu
Yanfen Wu
Jianfeng Cai
Xin-Shan Ye
Source :
Journal of Medicinal Chemistry. 4/12/2018, Vol. 61 Issue 7, p2865-2874. 10p.
Publication Year :
2018

Abstract

Antibiotic resistance is one of the biggest threats to public health, and new antibacterial agents hence are in an urgent need to combat infectious diseases caused by multidrug-resistant (MDR) pathogens. Utilizing dimerization strategy, we rationally designed and efficiently synthesized a new series of small molecule dimeric lysine alkylamides as mimics of AMPs. Evaluation of these mimics against a panel of Gram-positive and Gram-negative bacteria including MDR strains was performed, and a broad-spectrum and potent compound 3d was identified. This compound displayed high specificity toward bacteria over mammalian cell. Time-kill kinetics and mechanistic studies suggest that compound 3d quickly eliminated bacteria in a bactericidal mode by disrupting bacterial cell membrane. In addition, lead compound 3d could inhibit biofilm formation and did not develop drug resistance in S. aureus and E. coli over 14 passages. These results suggested that dimeric lysine nonylamide has immense potential as a new type of novel small molecular agent to combat antibiotic resistance. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00222623
Volume :
61
Issue :
7
Database :
Academic Search Index
Journal :
Journal of Medicinal Chemistry
Publication Type :
Academic Journal
Accession number :
129283365
Full Text :
https://doi.org/10.1021/acs.jmedchem.7b01704