Non-antimicrobial activity of macrolides : therapeutic potential in chronic inflammatory airway disorders

Abstract

In addition to their conventional antimicrobial activity, the macrolide group of antibiotics are known to have a number of anti-inflammatory/ immunomodulatory activities, which may be of benefit to patients with chronic obstructive pulmonary disease (COPD), both in the stable state and during acute exacerbations. These activities involve interactions of the macrolides with the various components of inflammation in patients with COPD, namely the ciliated airway epithelium, the immune and phagocytic cells of the host and their proinflammatory mediators, as well as with the microbes themselves. There are a number of factors that have been shown to cause injury to the bronchial epithelium and its mucociliary mechanism, including bacterial, chemical, mechanical and host-derived factors. The macrolide, azalide, ketolide group of antibiotics has been shown in many studies to be cytoprotective of human ciliated epithelium in vitro, protecting against both chemical mediator- and bacterial-mediated injury. Mucus hypersecretion is an important and characteristic feature of many respiratory diseases, including COPD, and increases the morbidity and mortality of these diseases especially as a consequence of pulmonary infection. Chronic inflammation causes not only airway damage, but also goblet cell hyperplasia, which leads to the mucus hypersecretion. Mediators of this inflammation include cytokines, chemokines and oxygen radicals. Both in vitro and in vivo studies have shown that macrolides reduce mucus and sputum secretion, which may also contribute to their beneficial effects on airway inflammation. Among many other anti-inflammatory actions, clarithromycin (and other macrolides) has been shown to interfere with the generation of neutrophil-selective chemoattractants by bronchial epithelial cells, eosinophils, monocytes, fibroblasts, and airway smooth muscle cells by mechanisms which appear to involve inhibition of intracellular signalling mechanisms. Macrolides also appear to selectively downregulate exuberant inflammatory responses which result from the interaction of viruses and Gram-negative bacteria with toll-like receptors, TLR3 and TLR4, respectively, while preserving the interaction of Gram-positive bacteria with TLR2. In addition to their standard antimicrobial activity, the macrolide group of antibiotics has been documented to have additional effects against bacteria which are not associated with inhibition of bacterial proliferation, and occur even in microorganisms that are totally resistant to their anti-proliferative actions. This has been most well studied in the case of Pseudomonas aeruginosa, a microorganism against which macrolides have no anti-proliferative activity. Macrolides have the ability to interfere with a number of virulence factors produced by P. aeruginosa. We have recently reported that the production of pneumolysin, a major protein virulence factor of Streptococcus pneumoniae, which promotes extra-pulmonary dissemination of this microorganism, is attenuated by exposure of the bacteria to sub-inhibitory concentrations of clarithromycin. Interestingly, clarithromycin-mediated inhibition of the production of penumolysin was observed not only with macrolide-susceptible strains of the pneumococcus, but also with macrolide-resistant strains which harboured either the ribosomal methylase (erm(B) gene)- or efflux pump (mef gene)-based mechanisms of macrolide resistance. Taken together, the evidence presented in this review, supports the contention that macrolides possess a seemingly unique profile of complementary therapeutic activities.