Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 20, Issue 15, Pages 4653-4660Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2012.06.018
Keywords
Staphylococcus aureus; Anti-MRSA agents; Anti-infection agents
Funding
- National Center for Research Resources [UL1RR025755]
- Office of the Director, National Institutes of Health (OD)
- NIH Roadmap for Medical Research
- National Science Council, Taiwan [NSC 99-2320-B-002-081, NSC 100-2320-B-002-104]
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Methicillin-resistant Staphylococcus aureus (MRSA) poses a serious threat to public health because of its resistance to multiple antibiotics most commonly used to treat infection. In this study, we report the unique ability of the cyclooxygenase-2 (COX-2) inhibitor celecoxib to kill Staphylococcus aureus and MRSA with modest potency. We hypothesize that the anti-Staphylococcus activity of celecoxib could be pharmacologically exploited to develop novel anti-MRSA agents with a distinct mechanism. Examination of an in-house, celecoxib-based focused compound library in conjunction with structural modifications led to the identification of compound 46 as the lead agent with high antibacterial potency against a panel of Staphylococcus pathogens and different strains of MRSA. Moreover, this killing effect is bacteria-specific, as human cancer cells are resistant to 46. In addition, a single intraperitoneal administration of compound 46 at 30 mg/kg improved the survival of MRSA-infected C57BL/6 mice. In light of its high potency in eradicating MRSA in vitro and its in vivo activity, compound 46 and its analogues warrant continued preclinical development as a potential therapeutic intervention against MRSA. (C) 2012 Elsevier Ltd. All rights reserved.
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