CHAPTER 6: Anti-Inflammatory Macrolides to Manage Chronic Neutrophilic Inflammation
Published:03 Oct 2014
Special Collection: 2014 ebook collection , 2011-2015 industrial and pharmaceutical chemistry subject collectionSeries: Drug Discovery
M. Burnet, J. Guse, H. Gutke, L. Guillot, S. Laufer, U. Hahn, ... M. J. Parnham, in Macrocycles in Drug Discovery, ed. J. Levin, The Royal Society of Chemistry, 2014, pp. 206-234.
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Macrolide antibiotics, notably azithromycin, have clinically useful effects in a range of inflammatory diseases and especially those of the lung. Effects include a reduction of inflammatory cytokines, reductions in neutrophil infiltration and potentially a polarisation of infiltrating cells to a pro-resolution phenotype. The mode of action behind this effect is unlikely to be a single interaction and may involve reductions in prostaglandin synthesis via phospholipase inhibition, modulation of NFκB translocation, reduction in IL-8 production and reduction in reflux aspiration to the airways. While some of the clinical effects can be rationalised through antibacterial actions leading to changes in normal flora and reducing Pseudomonads in particular, there is also evidence for effects unrelated to antibacterial actions that appear to relate to reductions in neutrophil activation, potentially related to high accumulation in neutrophil lysosomes. Concerted efforts to improve on these effects have focused on either generating non-antibacterial analogues, or in conjugating anti-inflammatory drugs to the macrolide backbone. Both approaches have provided strong pre-clinical data suggesting that the selective disposition of macrolides to inflamed tissue, as well as their pleiotropic effects on immune cells, contribute to their broad anti-inflammatory effects. The more recent observations of stronger macrolide effects in the context of neutrophil-mediated disease and corresponding effects on IL-17 positive cells in tissue suggest that it may be possible to select patients likely to respond to macrolide therapy. The discovery of non-antibacterial macrolides that preserve this anti-inflammatory effect provides a means to bring these effects more broadly to the clinic without selecting for large-scale resistance to antibacterial macrolides or to other anti-infectives via cross-resistance.