Repurposing celecoxib as a topical antimicrobial agent

Abstract

There is an urgent need for new antibiotics and alternative strategies to combat multidrug-resistant bacterial pathogens, which are a growing clinical issue. Repurposing existing approved drugs with known pharmacology and toxicology is an alternative strategy to accelerate antimicrobial research and development. In this study, we show that celecoxib, a marketed inhibitor of cyclooxygenase-2, exhibits broad-spectrum antimicrobial activity against Gram-positive pathogens from a variety of genera, including Staphylococcus, Streptococcus, Listeria, Bacillus, and Mycobacterium, but not against Gram-negative pathogens. However, celecoxib is active against all of the Gram-negative bacteria tested, including strains of, Acinetobacter, and Pseudomonas, when their intrinsic resistance is artificially compromised by outer membrane permeabilizing agents such as colistin. The effect of celecoxib on incorporation of radioactive precursors into macromolecules in Staphylococcus aureus was examined. The primary antimicrobial mechanism of action of celecoxib was the dose-dependent inhibition of RNA, DNA, and protein synthesis. Further, we demonstrate the in vivo efficacy of celecoxib in a methicillin-resistant S. aureus (MRSA) infected Caenorhabditis elegans whole animal model. Topical application of celecoxib (1 and 2%) significantly reduced the mean bacterial count in a mouse model of MRSA skin infection. Further, celecoxib decreased the levels of all inflammatory cytokines tested, including tumor necrosis factor-α, interleukin-6, interleukin-1 beta, and monocyte chemo attractant protein-1 in wounds caused by MRSA infection. Celecoxib also exhibited synergy with many conventional antimicrobials when tested against four clinical isolates of S. aureus. Collectively, these results demonstrate that celecoxib alone, or in combination with traditional antimicrobials, has a potential to use as a topical drug for the treatment of bacterial skin infections.

Repurposing auranofin for the treatment of cutaneous staphylococcal infections

“…All animal procedures were approved by the Purdue University Animal Care and Use Committee (West Lafayette, IN). An in vivo murine MRSA skin infection study was conducted as described elsewhere [2,22–24]. Briefly, mice (five mice per group) received an intradermal injection (40 μL) of MRSA USA300 containing 1.65 × 10 8 CFU.…”

Repurposing Approach Identifies Auranofin with Broad Spectrum Antifungal Activity That Targets Mia40-Erv1 Pathway

“…The concept of drug repositioning has recently gained momentum and emerged as a viable approach to expedite anti-infective drug development (Butts and Krysan, 2012; Thangamani et al, 2015a,b,c). For example, several reports have demonstrated that auranofin, an orally bioavailable FDA-approved drug for treatment of rheumatoid arthritis, exhibits potent antibacterial and antiparasitic activities (Jackson-Rosario et al, 2009; Debnath et al, 2012; Cassetta et al, 2014; Hokai et al, 2014; Aguinagalde et al, 2015; Thangamani et al, 2016a,b).…”

Celecoxib Alters the Intestinal Microbiota and Metabolome in Association with Reducing Polyp Burden

“…One study demonstrated that individuals who take NSAIDs have a different bacterial profile compared to those who do not take NSAIDs (20). Celecoxib also has direct antimicrobial activity, although it is not clear whether its chemopreventive action is related to its effects on microbiota or the metabolites they produce (21, 22). …”