ReviewAnti-inflammatory effects of macrolide antibiotics
Introduction
Macrolides are a well-established family of antibiotics isolated from streptomycetes. Their main characteristic is a macrocyclic lactone ring with one or two sugar moieties. They experienced a renaissance during the 1980s and 1990s, in which the commercial introduction of several semi-synthetic derivatives significantly expanded their therapeutic importance and utility. Among the most important characteristics of the macrolide antibiotics are a moderately broad spectrum of antibacterial activity, activity by oral administration and a relatively high therapeutic index. The first macrolide introduced into clinical practice was the 14-membered ring compound—erythromycin A. It was isolated from cultures of Streptomyces erythraea in 1952 (Washington et al., 1985; for review, see Mazzei et al., 1993, Williams and Sefton, 1993). The 15-membered macrolide antibiotic, azithromycin (a representative of the so-called azalides), has now become one of the most widely prescribed of all antibiotics. Macrolides like tylosine are widely used in veterinary medicine. The most recently synthesized macrolides are in late phase clinical development or approved for clinical use (e.g., the ketolides, ABT-773 and telithromycin). They are called ketolides because instead of sugar (l-cladinosyl moiety) at position 3 of the lactone ring these antibiotics have a keto-group (Wu, 2000). The principle advantage of this series of compounds is their activity against macrolide-resistant streptococci (Resek et al., 2000). For a recent review on anti-infective aspects of macrolides and particularly ketolides see Zhanel et al. (2001).
Structures of the most commonly used antibiotics are shown in Fig. 1. In addition to the chemical (semi-synthetic) approach to the development of new macrolide antibiotics, an alternative approach employing molecular biology techniques has also been used. Biotechnology permits the modification and interchange of specific parts of various biosynthetic gene clusters, like polyketide synthase, to produce new macrolide structures (Katz and Donadio, 1993). This process of artificial natural product formation is called recombinant biosynthesis Tsoi et al., 1995, Katz and McDaniel, 1999.
The mechanism of macrolide antibiotic action is based on inhibition of bacterial protein synthesis, by interacting with 23S rRNA in the central loop of the peptidyltransferase center as well as with specific ribosomal proteins found in the same region of the ribosome. Macrolides are best known as anti-infectives but also exert other important pharmacological effects such as immunosuppression and immunomodulation. For example, FK506 (tacrolimus) is a highly effective immunosuppressive drug used in organ transplantation and is one of the best immunosuppressive drugs available. This 23-membered macrolide lactone binds to FKBP 12 and modulates the calcineurin pathway. At subnanomolar concentrations it was shown to inhibit the proliferation of T cells stimulated by specific antigens (for review, see Dumont, 2000). Rapamycin (31-membered ring macrolide), although belonging to the same chemical class causes immunosuppression by a different mechanism. It forms an immunophilin complex that does not bind calcineurin and is therefore devoid of the calcineurin-related effects seen with FK506. Rapamycin was recently shown to inhibit apoptosis in human HL-60 cells (Johnson and Lawen, 1999).
Bafilomycin (16-membered macrolide) and concanamycin (18-membered macrolide) are the most potent specific inhibitors of vacuolar type H+-ATPase (for reviews, see Droese and Altendorf, 1997, Keeling et al., 1997, Gagliardi et al., 1999). Inhibition of the vacuolar H+-ATPase indirectly causes apoptotic cell death (Nishihara et al., 1995). Moreover, an intracellular apoptosis-inducing factor with a molecular mass of 33 kDa seems to be induced by concanamycin A treatment of (hybridoma) cells (Hashimoto et al., 2001). Oligomycin and apoptolidin are potent inhibitors of ATP-synthetase (F0F1-ATPase) and are among the most cytotoxic drugs for malignant cells Salomon et al., 2000, Salomon et al., 2001. There are also other scattered reports on macrolide actions which could not be classified as anti-bacterial, e.g. gastrointestinal motor stimulating activity (Omura et al., 1987), anti-cancer (Hamada et al., 2000) and anti-angiogenic effects Yatsunami et al., 1999a, Yatsunami et al., 1999b. Among the most peculiar ones are an anorexigenic reaction associated with weight loss (proposed for obesity treatment) and reduction of serum triglyceride levels with simultaneous increase in serum high-density lipoprotein (HDL) levels Klein, 1996, Klein, 2001.
In many cases, biological targets of macrolides remain unknown and still not sufficiently exploited. The techniques of proteomics and genomics could help to systematically explore targets with which various macrolides are capable of interacting (genes and/or proteins).
The main topic of this review is macrolides that influence targets of relevance for inflammatory processes. This is not a new topic and several excellent reviews have been written about these effects Gemmell, 1993, Wales and Woodhead, 1999, Labro, 1998a, Labro, 1998b, Rubin and Tamaoki, 2000, Labro, 2000, Labro and Abdelghaffar, 2001. The purpose of this review is to emphasize the most interesting newer findings, especially those that reveal the neutrophil as an important cellular target of macrolide action.
Section snippets
Inflammation
Most inflammatory diseases whether infective or non-infective in origin, are characterized by abnormal accumulation of inflammatory cells (including monocytes, macrophages, granulocytes, plasma cells, lymphocytes and platelets) that along with tissue endothelial cells and fibroblasts, release a complex array of lipid mediators, growth factors, cytokines and destructive enzymes that cause local tissue damage. Tissue damage in a group of neutrophil-dominated inflammatory diseases (bacterial
Cellular pharmacokinetics of macrolides
Additional interest in the therapeutic use of macrolide antibiotics has been based on the demonstration of their ability to concentrate within phagocytes. Macrolide antibiotics show unique and favorable cellular pharmacokinetic properties. The concentrations of azithromycin and clarithromycin, for instance, in the epithelial lung fluid normally tend to be at least 10-fold greater than simultaneously measured concentrations in the plasma or serum. These high concentrations often exceed the
Anti-inflammatory and other in-vitro effects of macrolides
A considerable body of evidence on in vitro effects of macrolides is present in the scientific literature. Nevertheless, these reports are sometimes contradictory. At least partially, the contradictions can be resolved by taking into account often very different experimental conditions (for review, see Labro and El Benna, 1993). Macrolide antibiotics modulate the functions of inflammatory cells, such as polymorphonuclear leukocytes, lymphocytes and macrophages Anderson, 1989, Roche et al., 1986
Healthy animals
There appear to be some differences between the effects of macrolides on inflammatory models and their effects on potentially inflammatory parameters in healthy animals. In the healthy guinea pig, roxithromycin increased airway ciliary activity after 14 days of oral administration. In addition, neutrophils in these animals exhibited increased superoxide production but their phagocytic activity remained unchanged (Sugiura et al., 1997). Ex vivo, it was shown that in healthy mice, a 28-day (but
Molecular targets of anti-inflammatory macrolides
In a recent milestone report (Aoki and Kao, 1999) erythromycin in vitro was shown to inhibit activation of the transcription factor NF-κB through a calcineurin-independent pathway. This is one of the first successful attempts to define the anti-inflammatory targets of the macrolide antibiotics at the molecular level. In a reporter gene assay, erythromycin at a concentration of 10−5 M inhibited interleukin-8 NF-κB transcription by 37%. It remains unclear whether the basis for inhibition lies in
Diffuse panbronchiolitis
In contrast to the large numbers of in vitro studies on anti-inflammatory effects of macrolide antibiotics, only a very limited number of clinical trials have been reported, and few in-vivo studies deal with the anti-inflammatory potential of macrolides. Some macrolide antibiotics like erythromycin, clarithromycin and roxithromycin have already been used as anti-inflammatory drugs, especially for the treatment of diffuse panbronchiolitis. Reports on the use of macrolides for diseases like
Conclusions
Over many years, macrolides have proven to be very effective antibacterial agents. Clinical and experimental data now indicate that the effects of macrolides are not just restricted to direct action on bacteria, but also involve modulation of host defense mechanisms. Phagocytes in particular appear to be important targets for macrolides. This is indicated by a decade of use of erythromycin in clinical treatment of diffuse panbronchiolitis. Effects of macrolides on host defense mechanism and/or
Acknowledgments
We would like to thank K. Brajša, V. Munić, W. Schönfeld and D. Verbanac for critical reading of the manuscript. We also thank M. Bosnar, S. Alihodžić and S.K. Kujundžić for their help in the preparation of the manuscript.
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