Development of novel antibacterial agents against methicillin-resistant Staphylococcus aureus
Journal
Bioorganic and Medicinal Chemistry
Journal Volume
20
Journal Issue
15
Pages
4653-4660
Date Issued
2012
Author(s)
Lee S.-L.
Kapuriya N.
Wang D.
Chen Y.-R.
Kulp S.K.
Chen C.-S.
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. ? 2012 Elsevier Ltd. All rights reserved.
SDGs
Other Subjects
4 (5 anthracen 9 yl 3 trifluoromethyl pyrazol 1 yl)benzamide; amoxicillin; ampicillin; antiinfective agent; celecoxib; chloramphenicol; n [4 (5 anthracen 2 yl 3 trifluoromethyl pyrazol 1 yl)phenyl]aminosulfonamide; n [4 (5 anthracen 9 yl 3 trifluoromethyl pyrazol 1 yl) phenyl]aminosulfonamide; n [4 (5 biphenyl 4 yl 3 trifluoromethyl pyrazol 1 yl) phenyl]aminosulfonamide; n [4 (5 naphthalen 2 yl 3 trifluoromethyl pyrazol 1 yl)phenyl]aminosulfonamide; n [4 (5 para tolyl 3 trifluoromethyl pyrazol 1 yl) phenyl]aminosulfonamide; n [4 (5 phenanthren 2 yl 3 trifluoromethyl pyrazol 1 yl)phenyl] aminosulfonamide; n [4 [5 (4' bromobiphenyl 4 yl) 3 trifluoromethyl pyrazol 1 yl]phenyl]aminosulfonamide; n [4 [5 (4' methylbiphenyl 4 yl) 3 trifluoromethyl pyrazol 1 yl]phenyl]aminosulfonamide; unclassified drug; animal experiment; animal model; antibacterial activity; article; bacterial strain; cancer cell; chemical modification; drug efficacy; drug potency; drug research; drug structure; drug synthesis; female; human; human cell; in vitro study; in vivo study; methicillin resistant Staphylococcus aureus; methicillin resistant Staphylococcus aureus infection; molecular library; mouse; nonhuman; single drug dose; species differentiation; Staphylococcus aureus; Animals; Anti-Bacterial Agents; Antineoplastic Agents; Cell Proliferation; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; HT29 Cells; Humans; Injections, Intraperitoneal; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Molecular Structure; Structure-Activity Relationship; methicillin resistant Staphylococcus aureus; Mus; Staphylococcus; Staphylococcus aureus
Type
journal article