title: In vitro and in vivo activity of a novel sorafenib derivative SC5005 against MRSA.
abstract: OBJECTIVE
  The emergence of MRSA strains resistant to most antibiotics is a serious threat to public health. Based on our discovery that the tyrosine kinase inhibitor sorafenib exhibits inhibitory activity against Staphylococcus species, the objective of this study is to exploit this unique antibacterial activity of sorafenib to develop novel antibacterial agents against MRSA.
  
  
  METHODS
  A sorafenib-based focused compound library was synthesized by substituting the pyridinyl and phenyl groups with different functional groups. The resulting sorafenib derivatives were screened for growth-suppressive activities against Staphylococcus aureus and Staphylococcus epidermidis following CLSI guidelines and for cytotoxicity towards human cells using MTT cell viability assays. Compounds with high selectivity for bacterial inhibition over cytotoxicity were further evaluated by time-kill assay and Caenorhabditis elegans and mice survival assays to evaluate their efficacy in vitro and in vivo.
  
  
  RESULTS
  The screening of sorafenib derivatives led to the identification of compound SC5005 as a lead compound with high potency in killing different clinical strains of MRSA with an MIC90 of 0.5 mg/L and with low cytotoxicity, as demonstrated by IC50-to-MIC ratios of up to 40. In addition, SC5005 showed a significant protective effect in MSSA- or MRSA-infected C. elegans. Intraperitoneal administration of SC5005 at 10 mg/kg significantly improved the survival of MRSA-infected C57BL/6 mice.
  
  
  CONCLUSIONS
  In light of its high potency in suppressing MRSA in both in vitro and in vivo models, SC5005 represents a potential lead agent for continued preclinical development as a therapeutic intervention against MRSA.
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan.
authors.forename: Han-Chu
authors.initials: HC
authors.lastname: Chang
authors.affiliation: Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Huang
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chang-Shi
authors.initials: CS
authors.lastname: Chen
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yi-Wei
authors.initials: YW
authors.lastname: Chen
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan.
authors.forename: Yu-Tsung
authors.initials: YT
authors.lastname: Huang
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan.
authors.forename: Jung-Chen
authors.initials: JC
authors.lastname: Su
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan.
authors.forename: Lee-Jeng
authors.initials: LJ
authors.lastname: Teng
authors.affiliation: Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chung-Wai
authors.initials: CW
authors.lastname: Shiau
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan hcchiu@ntu.edu.tw.
authors.forename: Hao-Chieh
authors.initials: HC
authors.lastname: Chiu
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000494:pharmacology* / Q000633:toxicity; D017173:Caenorhabditis elegans; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000494:pharmacology* / Q000633:toxicity; D000077157:Sorafenib; D013203:Staphylococcal Infections / Q000188:drug therapy*; D013212:Staphylococcus epidermidis / Q000187:drug effects; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib