Development of novel antibacterial agents against methicillin-resistant Staphylococcus aureus.

Abstract

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.

• Authors: Hao-Chieh Chiu, Su-Lin Lee, Naval Kapuriya, Dasheng Wang, Yi-Ru Chen, Sung-Liang Yu, Samuel K Kulp, Lee-Jene Teng, Ching-Shih Chen
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 20 Issue 15 Pg. 4653-60 (Aug 01 2012) ISSN: 1464-3391 [Electronic] England
• PMID: 22750009 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Anti-Bacterial Agents
• Antineoplastic Agents

Topics

• Animals
• Anti-Bacterial Agents (administration & dosage, chemical synthesis, pharmacology)
• Antineoplastic Agents (administration & dosage, chemical synthesis, pharmacology)
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Female
• HT29 Cells
• Humans
• Injections, Intraperitoneal
• Methicillin-Resistant Staphylococcus aureus (cytology, drug effects)
• Mice
• Mice, Inbred C57BL
• Microbial Sensitivity Tests
• Molecular Structure
• Structure-Activity Relationship