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Int. J. Mol. Sci. 2016, 17(11), 1934; doi:10.3390/ijms17111934

Design of New Antibacterial Enhancers Based on AcrB’s Structure and the Evaluation of Their Antibacterial Enhancement Activity

1
Department of Pharmacology, College of Pharmacy, The Third Military Medical University, Chongqing 400038, China
2
Department of Medicinal Chemistry, College of Pharmacy, The Third Military Medical University, Chongqing 400038, China
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editor: David Arráez-Román
Received: 22 June 2016 / Revised: 4 November 2016 / Accepted: 10 November 2016 / Published: 18 November 2016
(This article belongs to the Section Bioactives and Nutraceuticals)
View Full-Text   |   Download PDF [3654 KB, uploaded 18 November 2016]   |  

Abstract

Previously, artesunate (AS) and dihydroartemisinine 7 (DHA7) were found to have antibacterial enhancement activity against Escherichia coli via inhibition of the efflux pump AcrB. However, they were only effective against E. coli standard strains. This study aimed to develop effective antibacterial enhancers based on the previous work. Our results demonstrate that 86 new antibacterial enhancers were designed via 3D-SAR and molecular docking. Among them, DHA27 had the best antibacterial enhancement activity. It could potentiate the antibacterial effects of ampicillin against not only E. coli standard strain but also clinical strains, and of β-lactam antibiotics, not non-β-lactamantibiotics. DHA27 could increase the accumulation of daunomycin and nile red within E. coli ATCC 35218, but did not increase the bacterial membrane permeability. DHA27 reduced acrB’s mRNA expression of E. coli ATCC 35218 in a dose-dependent manner, and its antibacterial enhancement activity is related to the degree of acrB mRNA expression in E. coli clinical strains. The polypeptides from AcrB were obtained via molecular docking assay; the pre-incubated polypeptides could inhibit the activity of DHA27. Importantly, DHA27 had no cytotoxicity on cell proliferation. In conclusion, among newly designed antibacterial enhancers, DHA27 had favorable physical and pharmacological properties with no significant cytotoxicity at effective concentrations, and might serve as a potential efflux pump inhibitor in the future. View Full-Text
Keywords: antibacterial enhancer; AcrB inhibitor; DHA27; molecular mechanism antibacterial enhancer; AcrB inhibitor; DHA27; molecular mechanism
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Song, Y.; Qin, R.; Pan, X.; Ouyang, Q.; Liu, T.; Zhai, Z.; Chen, Y.; Li, B.; Zhou, H. Design of New Antibacterial Enhancers Based on AcrB’s Structure and the Evaluation of Their Antibacterial Enhancement Activity. Int. J. Mol. Sci. 2016, 17, 1934.

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