Identification of novel macrolides with antibacterial, anti-inflammatory and type I and III IFN-augmenting activity in airway epithelium

Abstract

BackgroundExacerbations of asthma and COPD are triggered by rhinoviruses. Uncontrolled inflammatory pathways, pathogenic bacterial burden and impaired antiviral immunity are thought to be important factors in disease severity and duration. Macrolides including azithromycin are often used to treat the above diseases, but exhibit variable levels of efficacy. Inhaled corticosteroids are also readily used in treatment, but may lack specificity. Ideally, new treatment alternatives should suppress unwanted inflammation, but spare beneficial antiviral immunity.MethodsIn the present study, we screened 225 novel macrolides and tested them for enhanced antiviral activity against rhinovirus, as well as anti-inflammatory activity and activity against Gram-positive and Gram-negative bacteria. Primary bronchial epithelial cells were grown from 10 asthmatic individuals and the effects of macrolides on rhinovirus replication were also examined. Another 30 structurally similar macrolides were also examined.ResultsThe oleandomycin derivative Mac5, compared with azithromycin, showed superior induction (up to 5-fold, EC50 = 5–11 μM) of rhinovirus-induced type I IFNβ, type III IFNλ1 and type III IFNλ2/3 mRNA and the IFN-stimulated genes viperin and MxA, yet had no effect on IL-6 and IL-8 mRNA. Mac5 also suppressed rhinovirus replication at 48 h, proving antiviral activity. Mac5 showed antibacterial activity against Gram-positive Streptococcus pneumoniae; however, it did not have any antibacterial properties compared with azithromycin when used against Gram-negative Escherichia coli (as a model organism) and also the respiratory pathogens Pseudomonas aeruginosa and non-typeable Haemophilus influenzae. Further non-toxic Mac5 derivatives were identified with various anti-inflammatory, antiviral and antibacterial activities.ConclusionsThe data support the idea that macrolides have antiviral properties through a mechanism that is yet to be ascertained. We also provide evidence that macrolides can be developed with anti-inflammatory, antibacterial and antiviral activity and show surprising versatility depending on the clinical need.

Not just the common cold: Rhinovirus infection in lung allograft recipients

“…The authors also evaluated the effects of pretreatment with azithromycin and found no effect on apoptosis but significant attenuation of both viral replication and virus-induced pro-inflammatory cytokine/chemokine responses. These findings confirm, in cells from lung transplant recipients, those previously reported in AEC from healthy subjects and patients with chronic airway disease [14][15][16] and likely relate to an augmentation of antiviral immunity by azithromycin rather than direct effects related to the amelioration of virus-induced cytotoxicity. Antiviral responses such as induction of type I and III interferons were not measured in the study by Ling et al, 19 and this represents an area of future interest.…”

“…11 Azithromycin is a macrolide antibiotic that is prescribed for acute respiratory tract infections and also has protective effects against infection when used prophylactically in patients with chronic lung disease. 12,13 In addition to antibacterial effects, there is increasing evidence from in vitro studies to indicate that macrolides can augment antiviral immunity [14][15][16] and thus may confer protection against RV infections. Azithromycin is also commonly used in the context of lung transplant recipients who develop BOS, an intervention that is supported by data from a clinical trial showing that azithromycin prophylaxis can improve forced expiratory volume in 1 s (FEV 1 ) following the establishment of BOS.…”

Antibacterial activity of a Tribolium castaneum defensin in an in vitro infection model of Streptococcus pneumoniae

“…The 5 h' time point simulated post-infection therapy, as it is common in primary care. Some antibacterial treatments have been described to act intrinsically immune-modulatory (e.g., macrolides [26]), others have been found to activate the immune system in a deleterious way by destroying the bacteria (e.g. the Jarisch-Herxheimer Reaction [27]).…”

Promising approaches for the treatment and prevention of viral respiratory illnesses

“…38 Novel macrolides (Mycobacterium avium complex 5) with anti-inflammatory, antibacterial, and, more importantly, interferon-augmenting activity in airway epithelium have been identified. 39 Finally, in vitro models have demonstrated that a 1 -antitrypsin exerts anti-inflammatory effects in airway epithelial cells from rhinovirus-infected patients with COPD, potentially through inhibition on caspase-1 activity, suggesting a 1 -antitrypsin as a potential anti-inflammatory agent. 40 extremely narrow.…”