title: Non-antibiotic agent ginsenoside 20(S)-Rh2 enhanced the antibacterial effects of ciprofloxacin in vitro and in vivo as a potential NorA inhibitor.
abstract: The aim of this study is to explore the potential enhancing effect of ginsenoside 20(S)-Rh2 (Rh2) towards ciprofloxacin (CIP) against Staphylococcus aureus (S. aureus) infection in vitro and in vivo, and analyze the possible mechanisms through NorA inhibition from a target cellular pharmacokinetic view. In combination with non-toxic dosage of Rh2, the susceptibilities of S. aureus strains to CIP were significantly augmented, and the antibacterial kinetics of CIP in the S. aureus strains were markedly promoted. This enhancing effect of Rh2 towards CIP was also observed in S. aureus infected peritonitis mice, with elevated survival rate and reduced bacteria counts in blood. However, Rh2 did not influence the plasma concentrations of CIP. Further analysis indicated that Rh2 significantly promoted the accumulations of CIP in S. aureus, and inhibited the NorA mediated efflux of pyronin Y. The expressions of NorA gene on S. aureus were positively correlated with the enhancing effect of Rh2 with CIP. This is the first report of the enhancing effect of Rh2 with CIP for S. aureus infection in vitro and in vivo, of which it is probably that Rh2 inhibited NorA-mediated efflux and promoted the accumulation of CIP in the bacteria.
authors: State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, China; Jiangsu Key laboratory of drug design and optimization, China Pharmaceutical University, Nanjing, Jiangsu, China.
authors: Jingwei
authors: J
authors: Zhang
authors: State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, China; Jiangsu Key laboratory of drug design and optimization, China Pharmaceutical University, Nanjing, Jiangsu, China.
authors: Yuan
authors: Y
authors: Sun
authors: State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, China; Jiangsu Key laboratory of drug design and optimization, China Pharmaceutical University, Nanjing, Jiangsu, China.
authors: Yaoyao
authors: Y
authors: Wang
authors: State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, China; Jiangsu Key laboratory of drug design and optimization, China Pharmaceutical University, Nanjing, Jiangsu, China.
authors: Meng
authors: M
authors: Lu
authors: State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, China; Jiangsu Key laboratory of drug design and optimization, China Pharmaceutical University, Nanjing, Jiangsu, China.
authors: Jichao
authors: J
authors: He
authors: State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, China; Jiangsu Key laboratory of drug design and optimization, China Pharmaceutical University, Nanjing, Jiangsu, China.
authors: Jiali
authors: J
authors: Liu
authors: State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, China; Jiangsu Key laboratory of drug design and optimization, China Pharmaceutical University, Nanjing, Jiangsu, China.
authors: Qianying
authors: Q
authors: Chen
authors: State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, China; Jiangsu Key laboratory of drug design and optimization, China Pharmaceutical University, Nanjing, Jiangsu, China.
authors: Xiaoxuan
authors: X
authors: Zhang
authors: State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, China; Jiangsu Key laboratory of drug design and optimization, China Pharmaceutical University, Nanjing, Jiangsu, China. Electronic address: zhoufangnjcpu@163.com.
authors: Fang
authors: F
authors: Zhou
authors: State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, China; Jiangsu Key laboratory of drug design and optimization, China Pharmaceutical University, Nanjing, Jiangsu, China. Electronic address: guangjiwang@hotmail.com.
authors: Guangji
authors: G
authors: Wang
authors: Division of Theoretical Chemistry and Biology, School of Biotechnology, KTH Royal Institute of Technology, S-106 91, Stockholm, Sweden.
authors: Xianqiang
authors: X
authors: Sun
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002939:Ciprofloxacin / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D004357:Drug Synergism; D036145:Ginsenosides / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010538:Peritonitis / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D011487:Protein Conformation; D011754:Pyronine / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002939:Ciprofloxacin; D036145:Ginsenosides; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011754:Pyronine; D012333:RNA, Messenger; C075040:NorA protein, Staphylococcus; C055305:ginsenoside Rh2
keywords: Bacteria resistance; Ciprofloxacin; Ginsenoside 20(S)-Rh2; NorA efflux pump; Staphylococcus aureus