title: Design of New Antibacterial Enhancers Based on AcrB's Structure and the Evaluation of Their Antibacterial Enhancement Activity.
abstract: Previously, artesunate (AS) and dihydroartemisinine 7 (DHA7) were found to have antibacterial enhancement activity againstEscherichia colivia inhibition of the efflux pump AcrB. However, they were only effective againstE. colistandard 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 onlyE. colistandard strain but also clinical strains, and of β-lactam antibiotics, not non-β-lactamantibiotics. DHA27 could increase the accumulation of daunomycin and nile red withinE. coliATCC 35218, but did not increase the bacterial membrane permeability. DHA27 reducedacrB's mRNA expression ofE. coliATCC 35218 in a dose-dependent manner, and its antibacterial enhancement activity is related to the degree ofacrBmRNA expression inE. coliclinical 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.
authors.affiliation: Department of Pharmacology, College of Pharmacy, The Third Military Medical University, Chongqing 400038, China. songyi19890126@163.com.
authors.forename: Yi
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Pharmacology, College of Pharmacy, The Third Military Medical University, Chongqing 400038, China. michel_0415@163.com.
authors.forename: Rongxin
authors.initials: R
authors.lastname: Qin
authors.affiliation: Department of Pharmacology, College of Pharmacy, The Third Military Medical University, Chongqing 400038, China. xichunpan@163.com.
authors.forename: Xichun
authors.initials: X
authors.lastname: Pan
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, The Third Military Medical University, Chongqing 400038, China. ouyangq@tmmu.edu.cn.
authors.forename: Qin
authors.initials: Q
authors.lastname: Ouyang
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, The Third Military Medical University, Chongqing 400038, China. liutianyu@tmmu.edu.cn.
authors.forename: Tianyu
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, College of Pharmacy, The Third Military Medical University, Chongqing 400038, China. zzzhaoxia@sina.com.
authors.forename: Zhaoxia
authors.initials: Z
authors.lastname: Zhai
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, The Third Military Medical University, Chongqing 400038, China. ycchen@scu.edu.cn.
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, College of Pharmacy, The Third Military Medical University, Chongqing 400038, China. libin6033@sina.com.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Pharmacology, College of Pharmacy, The Third Military Medical University, Chongqing 400038, China. zhouh64@163.com.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D037621:Artemisinins / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004357:Drug Synergism; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000072417:Protein Domains; D013329:Structure-Activity Relationship; D047090:beta-Lactams / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D037621:Artemisinins; D029968:Escherichia coli Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D047090:beta-Lactams; C083496:AcrB protein, E coli; C039060:artenimol
keywords: AcrB inhibitor; DHA27; antibacterial enhancer; molecular mechanism