Celecoxib Sensitizes Staphylococcus aureus to Antibiotics in Macrophages by Modulating SIRT1

Abstract

We have previously shown that celecoxib in combination with an antibiotic, increase the bacterial sensitivity to antibiotics. However, the underlying molecular mechanism remained elusive. Efficacy of the combinatorial treatment of celecoxib and ampicillin in vitro was evaluated on macrophage-phagocytosed S aureus. To elucidate the mechanism, signaling pathway of infection and inflammation involving TLR2, JNK, SIRT1 and NF-κB was studied by FACS, Western blot, ELISA and activity assays. Combinatorial treatment of ampicillin and celecoxib reduced the bacterial load in the macrophages. Further studies clearly suggested the activation of the master regulator of oxidative stress and inflammation SIRT1,, by celecoxib when used alone and/or in combination with ampicillin. Also, the results indicated that celecoxib inhibited JNK phosphorylation thereby stabilizing and activating SIRT1 protein that inhibited the COX-2 gene transcription with a significant decrease in the levels of protein inflammatory cytokines like IL-6, MIP-1α and IL-1β via inhibition of NF-κB. SIRT1 activation by celecoxib also resulted in increase of catalase and peroxidase activity with a decrease in Nitric oxide levels. In conclusion, we demonstrate a novel role of celecoxib in controlling inflammation as an enhancer of antibiotic activity against bacteria by modulating SIRT1.

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“…56 Non-steroidal anti-inflammatory drugs are a class of drugs that inhibit COX2 enzyme activity and thereby reduce the inflammatory response. 57,58 This supports the notion that SN30028 has antiinflammatory effects.…”

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“…Similarly, sirtuin-deficient mice have been shown to demonstrate improved intestinal anti-bacterial defense mechanisms (Lo Sasso et al, 2014). On the other hand, the use of celecoxib to stimulate sirtuin 1 within macrophages resulted in an enhanced ability of ampicillin to clear Staphylococcus aureus from these cells (Annamanedi and Kalle, 2014), consistent with the observation that low levels of sirtuin 1 within macrophages associates with bacterial infection in these cells (Zhang et al, 2010a(Zhang et al, , 2010b. Sirtuin 1 also appears to be essential for optimal immune clearance of respiratory syncytial virus and has been shown to suppress human T-cell leukemia virus type 1 transcription (Owczarczyk et al, 2015;Tang et al, 2015).…”

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“…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 ). However, the antibacterial mechanism of action of celecoxib and its potential clinical application remain underexplored.…”