N′-Substituted-2′-O,3′-N-carbonimidoyl Bridged Macrolides: Novel Anti-inflammatory Macrolides without Antimicrobial Activity

Bosnar, Martina; Kragol, Goran; Koštrun, Sanja; Vujasinović, Ines; Bošnjak, Berislav; Mihaljević, Vlatka Bencetić; Ištuk, Zorica Marušić; Kapić, Samra; Hrvačić, Boška; Brajša, Karmen; Tavčar, Branka; Jelić, Dubravko; Glojnarić, Ines; Verbanac, Donatella; Čulić, Ognjen; Padovan, Jasna; Alihodžić, Sulejman; Haber, Vesna Eraković; Spaventi, Radan

doi:10.1021/jm300356u

Cited by 27 publications

(20 citation statements)

References 44 publications

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“…Another approach to lessen the resistance burden is the design of macrolides that have their antimicrobial activities completely abolished but have other activities retained. It appears that the antimicrobial and anti-inflammatory activities of macrolides are independent and can be separated, thus opening the possibility of designing macrolide-based anti-inflammatory drugs lacking antimicrobial activities (Bosnar et al, 2012). …”

Section: Macrolidesmentioning

confidence: 99%

Biotic acts of antibiotics

Aminov¹

2013

Front. Microbiol.

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Biological functions of antibiotics are not limited to killing. The most likely function of antibiotics in natural microbial ecosystems is signaling. Does this signaling function of antibiotics also extend to the eukaryotic – in particular mammalian – cells? In this review, the host modulating properties of three classes of antibiotics (macrolides, tetracyclines, and β-lactams) will be briefly discussed. Antibiotics can be effective in treatment of a broad spectrum of diseases and pathological conditions other than those of infectious etiology and, in this capacity, may find widespread applications beyond the intended antimicrobial use. This use, however, should not compromise the primary function antibiotics are used for. The biological background for this inter-kingdom signaling is also discussed.

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Section: Macrolidesmentioning

confidence: 99%

Biotic acts of antibiotics

Aminov¹

2013

Front. Microbiol.

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“…In efforts to improve efficacy and/or reduce the risk of increasing antibiotic resistance, researchers are evaluating the immunomodulatory potential of AZM derivatives and other macrolide derivatives with the goal of separating the antibiotic from immunomodulatory properties. As a result, some macrolide derivatives have been shown to retain immunomodulatory properties in models of lung inflammation, inflammatory bowel diseases, arthritis, and skin inflammation . The ability of macrolide derivatives to reduce macrophage‐mediated neurotoxicity, however, is unknown.…”

Section: Introductionmentioning

confidence: 99%

“…As a result, some macrolide derivatives have been shown to retain immunomodulatory properties in models of lung inflammation, inflammatory bowel diseases, arthritis, and skin inflammation. [13][14][15][16][17][18] The ability of macrolide derivatives to reduce macrophage-mediated neurotoxicity, however, is unknown. With the increased use of AZM as an immunomodulatory agent for macrophage-mediated neurotoxicity in CNS pathologies, our goal in the present study was to determine whether macrolide derivatives retain neuroprotective properties.…”

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confidence: 99%

Macrolide derivatives reduce proinflammatory macrophage activation and macrophage‐mediated neurotoxicity

et al. 2019

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Summary Introduction Azithromycin (AZM) and other macrolide antibiotics are applied as immunomodulatory treatments for CNS disorders. The immunomodulatory and antibiotic properties of AZM are purportedly independent. Aims To improve the efficacy and reduce antibiotic resistance risk of AZM‐based therapies, we evaluated the immunomodulatory and neuroprotective properties of novel AZM derivatives. We semisynthetically prepared derivatives by altering sugar moieties established as important for inhibiting bacterial protein synthesis. Bone marrow‐derived macrophages (BMDMs) were stimulated in vitro with proinflammatory, M1, stimuli (LPS + INF‐gamma) with and without derivative costimulation. Pro‐ and anti‐inflammatory cytokine production, IL‐12 and IL‐10, respectively, was quantified using ELISA. Neuron culture treatment with BMDM supernatant was used to assess derivative neuroprotective potential. Results Azithromycin and some derivatives increased IL‐10 and reduced IL‐12 production of M1 macrophages. IL‐10/IL‐12 cytokine shifts closely correlated with the ability of AZM and derivatives to mitigate macrophage neurotoxicity. Conclusions Sugar moieties that bind bacterial ribosomal complexes can be modified in a manner that retains AZM immunomodulation and neuroprotection. Since the effects of BMDMs in vitro are predictive of CNS macrophage responses, our results open new therapeutic avenues for managing maladaptive CNS inflammation and support utilization of IL‐10/12 cytokine profiles as indicators of macrophage polarization and neurotoxicity.

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“…In compounds where the desosamine interactions are blocked, such as those shown in Figure 6.3, molecular weights are typically in the range of 800 to 1100. 24 …”

Section: Reducing Antibacterial Effects Of 14-and 15-membered Macrolamentioning

confidence: 99%

Anti-Inflammatory Macrolides to Manage Chronic Neutrophilic Inflammation

Burnet

Guse

Gutke

et al. 2014

Macrocycles in Drug Discovery

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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.

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N′-Substituted-2′-O,3′-N-carbonimidoyl Bridged Macrolides: Novel Anti-inflammatory Macrolides without Antimicrobial Activity

Cited by 27 publications

References 44 publications

Biotic acts of antibiotics

Biotic acts of antibiotics

Macrolide derivatives reduce proinflammatory macrophage activation and macrophage‐mediated neurotoxicity

Anti-Inflammatory Macrolides to Manage Chronic Neutrophilic Inflammation

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