title: Tetrandrine reverses drug resistance in isoniazid and ethambutol dual drug-resistant Mycobacterium tuberculosis clinical isolates.
abstract: BACKGROUND
  Tetrandrine is a natural chemical product purified from fourstamen stephania root which recently has been shown to act similarly as synthesized drug efflux pump inhibitor verapamil. The aim of the study is to examine whether tetrandrine could potentiate anti-tubercular drugs to which Mycobacterium tuberculosis (MTB) has turned resistant via efflux mechanisms.
  
  
  METHODS
  We screened 200 MTB clinical isolates using drug sensitivity test to look for those who have turned resistant to the drugs most probably due to efflux mechanisms. We found 29 isoniazid (INH) and ethambutol (EMB) - dual resistant (IEDR) strains. Then we tested if treatment with tetrandrine or verapamil could reverse drug resistance to INH and/or EMB in IEDR isolates.
  
  
  RESULTS
  There is a parallel resistance among EMB- and INH-resistant strains in the tested clinical isolates. Among INH-resistant strains, 65% was also EMB-resistant. This suggests an involvement of efflux mechanisms which can lead to dual drug resistance in IEDR clinical isolates. Similar to a synthesized efflux pump inhibitor verapamil, tetrandrine treatment together with INH or EMB brought down the MICs from the clinical level of drug resistance to the sensitive range of both drugs. The effective rate reached 82% among IEDR clinical isolates.
  
  
  CONCLUSIONS
  Combinational application of tetrandrine with INH or EMB increased drug efficacy. Drugs like tetrandrine may help to reduce drug dosage thus alleviate side effects.
authors.affiliation: Research Center of Infection and Immunity, Department of Microbiology and Parasitology, School of Basic Medical Sciences, School of Medicine, Zhejiang University, Hangzhou, China. 18758892040@163.com.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Research Center of Infection and Immunity, Department of Microbiology and Parasitology, School of Basic Medical Sciences, School of Medicine, Zhejiang University, Hangzhou, China. med_bp@zju.edu.cn.
authors.forename: Jie
authors.initials: J
authors.lastname: Yan
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital of School of Medicine, Zhejiang University, 15th floor, Building 6A, No. 79 Qingchun Road, Shangcheng District, Hangzhou, 310003, Zhejiang Province, China. zdyxyxukaijin@163.com.
authors.forename: Kaijin
authors.initials: K
authors.lastname: Xu
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital of School of Medicine, Zhejiang University, 15th floor, Building 6A, No. 79 Qingchun Road, Shangcheng District, Hangzhou, 310003, Zhejiang Province, China. 15068179504@163.com.
authors.forename: Zhongkang
authors.initials: Z
authors.lastname: Ji
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital of School of Medicine, Zhejiang University, 15th floor, Building 6A, No. 79 Qingchun Road, Shangcheng District, Hangzhou, 310003, Zhejiang Province, China. ljli@zju.edu.cn.
authors.forename: Lanjuan
authors.initials: L
authors.lastname: Li
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D044182:Benzylisoquinolines / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial; D004357:Drug Synergism; D004977:Ethambutol / Q000494:pharmacology; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D018088:Tuberculosis, Multidrug-Resistant / Q000382:microbiology*
chemical_list: D000995:Antitubercular Agents; D044182:Benzylisoquinolines; C009438:tetrandrine; D004977:Ethambutol; D007538:Isoniazid