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.
Highlights
Microbial drug resistance is of increasing concern and in the light of time and cost incurred in the novel drug development; the current research is focused on identifying alternate therapies by drug repurposing and repositioning
To demonstrate the in vitro efficacy of combinatorial treatment of ampicillin and celecoxib on phagocytosed S aureus, we first evaluated the effect of Non-steroidal Anti-Inflammatory Drugs (NSAIDs) alone on the growth of S aureus bacteria
The results indicated no inhibitory effect of NSAIDs on the growth of bacteria (Fig. 1A)
Summary
Microbial drug resistance is of increasing concern and in the light of time and cost incurred in the novel drug development; the current research is focused on identifying alternate therapies by drug repurposing and repositioning. We have shown that celecoxib, a cyclooxygenase-2 (COX-2)-specific inhibitor, in combination with an antibiotic increased bacterial sensitivity to the antibiotic [1]. It has been demonstrated that a combination therapy using antibiotics and already approved drugs can overcome bacterial resistance [2]. In vitro effect of such combination therapy on phagocytosed bacteria and the underlying molecular mechanism is not yet demonstrated. Role of human SIRT1 in inflammation and as oxidative stress regulator has been demonstrated [3,4,5,6,7]. SIRT1 regulates proinflammatory gene expression including COX-2, TNF-a, interleukins etc. It was demonstrated that SIRT1 is down regulated and COX-2 is over expressed in macrophages infected with bacteria [3,8]
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