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Research ArticleInflammation, Immunopharmacology, and Asthma

A Novel Macrolide Solithromycin Exerts Superior Anti-inflammatory Effect via NF-κB Inhibition

Yoshiki Kobayashi, Hiroo Wada, Christos Rossios, Dai Takagi, Manabu Higaki, Shin'ichiro Mikura, Hajime Goto, Peter J. Barnes and Kazuhiro Ito
Journal of Pharmacology and Experimental Therapeutics April 2013, 345 (1) 76-84; DOI: https://doi.org/10.1124/jpet.112.200733
Yoshiki Kobayashi
Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom (Y.K., C.R., D.T., P.J.B., K.I.); and Department of Respiratory Medicine, Kyorin University, School of Medicine, Tokyo, Japan (H.W., M.H., S.M., H.G.)
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Hiroo Wada
Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom (Y.K., C.R., D.T., P.J.B., K.I.); and Department of Respiratory Medicine, Kyorin University, School of Medicine, Tokyo, Japan (H.W., M.H., S.M., H.G.)
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Christos Rossios
Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom (Y.K., C.R., D.T., P.J.B., K.I.); and Department of Respiratory Medicine, Kyorin University, School of Medicine, Tokyo, Japan (H.W., M.H., S.M., H.G.)
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Dai Takagi
Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom (Y.K., C.R., D.T., P.J.B., K.I.); and Department of Respiratory Medicine, Kyorin University, School of Medicine, Tokyo, Japan (H.W., M.H., S.M., H.G.)
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Manabu Higaki
Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom (Y.K., C.R., D.T., P.J.B., K.I.); and Department of Respiratory Medicine, Kyorin University, School of Medicine, Tokyo, Japan (H.W., M.H., S.M., H.G.)
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Shin'ichiro Mikura
Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom (Y.K., C.R., D.T., P.J.B., K.I.); and Department of Respiratory Medicine, Kyorin University, School of Medicine, Tokyo, Japan (H.W., M.H., S.M., H.G.)
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Hajime Goto
Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom (Y.K., C.R., D.T., P.J.B., K.I.); and Department of Respiratory Medicine, Kyorin University, School of Medicine, Tokyo, Japan (H.W., M.H., S.M., H.G.)
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Peter J. Barnes
Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom (Y.K., C.R., D.T., P.J.B., K.I.); and Department of Respiratory Medicine, Kyorin University, School of Medicine, Tokyo, Japan (H.W., M.H., S.M., H.G.)
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Kazuhiro Ito
Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom (Y.K., C.R., D.T., P.J.B., K.I.); and Department of Respiratory Medicine, Kyorin University, School of Medicine, Tokyo, Japan (H.W., M.H., S.M., H.G.)
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Abstract

Macrolides are reported to reduce exacerbation of chronic inflammatory respiratory disease, such as chronic obstructive pulmonary disease (COPD), and also show anti-inflammatory effects in vitro and in vivo. However the anti-inflammatory efficacies of current macrolides are relatively weak. Here we found that a novel macrolide/fluoroketolide solithromycin (CEM-101) showed superior anti-inflammatory effects to macrolides in current clinical use. The effects of solithromycin (SOL) on lipopolysaccharide-induced TNFα (tumor necrosis factor α) and/or CXCL8 (C-X-C motif chemokine ligand 8; interleukin-8) release, phorbol 12-myristate 13-acetate-induced MMP9 (matrix metalloproteinase 9) activity and NF-κB (nuclear factor-κB) activity under conditions of oxidative stress have been evaluated and compared with the effects of erythromycin, clarithromycin, azithromycin, and telithromycin in macrophage-like PMA-differentiated U937 cells and peripheral blood mononuclear cells (PBMC) obtained from COPD patients. We also examined effect of SOL on cigarette smoke-induced airway inflammation in mice. SOL exerted superior inhibitory effects on TNFα/CXCL8 production and MMP9 activity in monocytic U937 cells. In addition, SOL suppressed TNFα release and MMP9 activity in PBMC from COPD patients at 10 µM, which is 10 times more potent than the other macrolides tested. Activated NF-κB by oxidative stress was completely reversed by SOL. SOL also inhibited cigarette smoke-induced neutrophilia and pro-MMP9 production in vivo, although erythromycin did not inhibit them. Thus, SOL showed better anti-inflammatory profiles compared with macrolides currently used in the clinic and may be a promising anti-inflammatory and antimicrobial macrolide for the treatment of COPD in future.

Footnotes

    • Received September 28, 2012.
    • Accepted December 20, 2012.
  • This work was supported by a project grant from Cempra Pharmaceuticals, Inc. K.I. is currently employed by RespiVert Ltd. and has an honorary contract with Imperial College. P.J.B. has served on Scientific Advisory Boards of AstraZeneca, Boehringer-Ingelheim, Chiesi, Respivert, Daiichi-Sankyo, GlaxoSmithKline, Novartis, Nycomed, Pfizer, Teva and UCB and has received research funding from Aquinox Pharmaceutiocals, AstraZeneca, Boehringer-Ingelheim, Chiesi, Daiichi-Sankyo, GlaxoSmithKline, Novartis, Nycomed, Pfizer and Prosonix. The other authors have declared that no competing interests exist for this research.

  • dx.doi.org/10.1124/jpet.112.200733.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 345 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 345, Issue 1
1 Apr 2013
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Research ArticleInflammation, Immunopharmacology, and Asthma

Anti-inflammatory Effect of Solithromycin

Yoshiki Kobayashi, Hiroo Wada, Christos Rossios, Dai Takagi, Manabu Higaki, Shin'ichiro Mikura, Hajime Goto, Peter J. Barnes and Kazuhiro Ito
Journal of Pharmacology and Experimental Therapeutics April 1, 2013, 345 (1) 76-84; DOI: https://doi.org/10.1124/jpet.112.200733

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Research ArticleInflammation, Immunopharmacology, and Asthma

Anti-inflammatory Effect of Solithromycin

Yoshiki Kobayashi, Hiroo Wada, Christos Rossios, Dai Takagi, Manabu Higaki, Shin'ichiro Mikura, Hajime Goto, Peter J. Barnes and Kazuhiro Ito
Journal of Pharmacology and Experimental Therapeutics April 1, 2013, 345 (1) 76-84; DOI: https://doi.org/10.1124/jpet.112.200733
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