In vitro and in vivo activity of a novel sorafenib derivative SC5005 against MRSA
Journal
Journal of Antimicrobial Chemotherapy
Journal Volume
71
Journal Issue
2
Pages
449_459
Date Issued
2016
Author(s)
Abstract
Objectives: 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. ? The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
SDGs
Other Subjects
ampicillin; antiinfective agent; chloramphenicol; erythromycin; functional group; ofloxacin; phenyl group; pyridine derivative; rifampicin; sc 5005; sc 72; sc 78; sc 79; sc 80; sorafenib; sorafenib derivative; tetracycline; unclassified drug; vancomycin; antiinfective agent; carbanilamide derivative; nicotinamide; animal experiment; animal model; antibacterial activity; antiproliferative activity; Article; bacterial strain; Caenorhabditis elegans; cell viability assay; controlled study; drug cytotoxicity; drug efficacy; drug screening; drug selectivity; female; human; human cell; IC50; in vitro study; in vivo study; methicillin resistant Staphylococcus aureus; methicillin resistant Staphylococcus aureus infection; MIC50; mouse; MTT assay; nonhuman; Staphylococcus epidermidis; structure activity relation; survival; analogs and derivatives; animal; C57BL mouse; cell line; cell survival; disease model; drug effects; methicillin resistant Staphylococcus aureus; microbial sensitivity test; Staphylococcal Infections; survival analysis; treatment outcome; Animals; Anti-Bacterial Agents; Caenorhabditis elegans; Cell Line; Cell Survival; Disease Models, Animal; Female; Humans; Inhibitory Concentration 50; Methicillin-Resistant Staphylococcus aureus; Mice, Inbred C57BL; Microbial Sensitivity Tests; Niacinamide; Phenylurea Compounds; Staphylococcal Infections; Staphylococcus epidermidis; Survival Analysis; Treatment Outcome
Type
journal article