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.

Repurposing celecoxib as a topical antimicrobial agent

“…Another study by Chiu et al (2009) found that celecoxib inhibited the growth of Francisella tularensis and F. novicida . In addition, celecoxib also exhibited antibacterial activity against S. aureus and S. epidermidis ( Chiu et al, 2012 ). Apart from antimicrobial activity, celecoxib inhibits multidrug efflux pumps in Mycobacterium smegmatis and S. aureus , and increases the sensitivity of bacteria to various antibiotics, including ampicillin, kanamycin, ciprofloxacin, and chloramphenicol ( Kalle and Rizvi, 2011 ; Annamanedi and Kalle, 2014 ).…”

Identification of Small-Molecule Inhibitors of Brucella Diaminopimelate Decarboxylase by Using a High-Throughput Screening Assay

“…Among them are SID 3 (dasatinib monohydrate), a new kind of multitargeted inhibitor of several critical oncogenic kinases for the treatment of thyroid cancer (Roy et al, 2012); SID4 (carboplatin), a kind of antineoplastic agent used mainly for the treatment of human cancer via interfering with DNA synthesis (Banerji et al, 2008); SID14 (ulixertinib, BVD-523), a highly potent, selective, and reversible ERK1/2 inhibitor used for the treatment of advanced solid tumors (Mendzelevski et al, 2018); SID 15 (pimobendan), a phosphodiesterase III inhibitor used for the treatment of chronic and acute heart failure (Iwasaki et al, 1999); and SID 20 (tolfenamic acid), a traditional antiinflammatory compound that acts as a kind of cyclooxygenase inhibitor commonly used for the treatment of inflammationrelated diseases (Feldman et al, 2018). However, researchers recently found new applications for cyclooxygenase inhibitors, such as celecoxib, that possess bactericidal effects against some pathogenic bacteria (such as Staphylococcus aureus, Bacillus anthracis, and Pseudomonas aeruginosa) (Chiu et al, 2012;Thangamani et al, 2015). The new application of conventionally approved drugs has recently received increasing attention.…”

Advances in MRSA drug discovery: where are we and where do we need to be?

“…Several clinical options that currently exist to treat MRSA are summarized in Introduction [173]. MRSA treatment guideline was prepared by an Expert Panel of the Infectious Diseases Society of America (IDSA) [174].…”