Anti-Inflammatory Macrolides to Manage Chronic Neutrophilic Inflammation

Abstract

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.

Synthesis, Characterization, and in vivo Distribution of Intracellular Delivered Macrolide Short‐Chain Fatty Acid Derivatives

“…Esters are well known to hydrolyze chemically, or via esterases or lipases, and our earlier work had demonstrated the lability of the 2' esters. [22,23] To ensure that the compounds could be prepared and stored in a stable form we investigated their stability in solution under various conditions and to support analysis of possible pharmacokinetic studies. In particular, the 2' position of Azithromycin interacts with the bacterial ribosome.…”

“…The substances we describe here are active in the range of 0.1 mg/kg and are thus much more efficient than free SCFAs. [22,23] Sensing of SCFAs appears to take place at several levels. Colonocytes have surface receptors which appear to regulate tight junction formation and density.…”

“…While the technology for widespread therapy with microorganisms is developing, a simplified small molecule approach that simulates a healthy microbiome may be one means to use knowledge and to mimic the microbiome in the treatment of gut disorders. The substances we describe here are active in the range of 0.1 mg/kg and are thus much more efficient than free SCFAs [22,23] …”

Pharmacokinetic Optimization of Small Molecule Janus Kinase 3 Inhibitors to Target Immune Cells

“…47,48 Through modifications to the macrolide structure, e.g., removal of the cladinose sugar or introduction of bulky residues to the desosamine, the carriers' antibiotic properties can be reduced, thus avoiding potential selection for bacterial macrolide resistance. 49 We used azithromycin as a model compound for the carrier due to its metabolic stability and high ratio of tissue to serum concentration. 68 Also, compared to erythromycin, the azalide is considerably more resistant to acidic conditions in the stomach and has less affinity for human ether-a-go-go-related gene (hERG) channels, the inhibition of which could result in long QT syndrome.…”

Nonantimicrobial Actions of Macrolides: Overview and Perspectives for Future Development

“…When the modified macrolide space is analyzed, many of the published nonantibiotic macrolides have closely followed erythromycin in their design, with anti-inflammatory effects being used to select the molecules. Some 15-membered derivatives exhibiting anti-inflammatory effects in preclinical models have also been described (Erakovic Haber et al, 2014;Burnet et al, 2015). Some developers have also described 12-membered macrolactones with immunomodulatory properties and anti-inflammatory effects as potential therapeutic agents, but to date, there are no reported clinical trials with such drugs (Sugawara et al, 2011(Sugawara et al, , 2012(Sugawara et al, , 2016.…”