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Bioorg Med Chem. 2019 Apr 1;27(7):1274-1282. doi: 10.1016/j.bmc.2019.02.024. Epub 2019 Feb 14.

Antibacterial activity of indolyl-quinolinium derivatives and study their mode of action.

Author information

1
School of Chemical Engineering and Light Industry, School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, PR China.
2
The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510700, PR China.
3
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, PR China.
4
School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, PR China.
5
The State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China.
6
School of Chemical Engineering and Light Industry, School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, PR China. Electronic address: luyj@gdut.edu.cn.
7
School of Chemical Engineering and Light Industry, School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, PR China; The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510700, PR China; The State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China. Electronic address: ning.sun@connect.polyu.hk.

Abstract

Filamenting temperature-sensitive mutant Z (FtsZ) is recognized as a promising target for new antibiotics development because of its high conservatism and pivotal role in the bacteria cell division. The aromatic heterocyclic scaffold of indole is known showing merit medical functions in antiviral and antimicrobial. In the present study, a series of 1-methylquinolinium derivatives, which were integrated with an indole fragment at its 2-position and a variety of amino groups (cyclic or linear, mono- or di-amine) at the 4-position were synthesized and their antibacterial activities were evaluated. The results of antibacterial study show that the representative compounds can effectively inhibit the growth of testing strains including MRSA and VRE, with MIC values of 1-4 μg/mL by bactericidal mode. The mode of action assays revealed that c2 can effectively disrupt the rate of GTP hydrolysis and dynamic polymerization of FtsZ, and thus inhibits bacterial cell division and then causes bacterial cell death. In addition, the result of resistance generation experiment reveals that c2 is not likely to induce resistance in S. aureus.

KEYWORDS:

Antibacterial activity; Cells division; Drug resistant bacteria; FtsZ; Indolyl quinolinium derivatives

PMID:
30792100
DOI:
10.1016/j.bmc.2019.02.024

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