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

J. Antimicrob. Chemother. (2016)doi: 10.1093/jac/dkw222

James D. Porter1,2, 

Jennifer Watson1, 

Lee R. Roberts3, 

Simren K. Gill4, 

Helen Groves4,

Jaideep Dhariwal1,2, 

Mark H. Almond1,2, 

Ernie Wong1,2, 

Ross P. Walton1,2, 

Lyn H. Jones3, 

John Tregoning4, 

Iain Kilty3, 

Sebastian L. Johnston1,2 and 

Michael R. Edwards1,2,*

Author Affiliations

1. ¹Airway Disease Infection Section, National Heart Lung Institute, Imperial College London, London, UK
2. ²MRC & Asthma UK Centre for Allergic Mechanisms of Asthma, London, UK
3. ³Pfizer Inc., Cambridge, MA, USA
4. ⁴Mucosal Infection and Immunity Group, Section of Virology, Imperial College London, London, UK

 

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Abstract

Background Exacerbations 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.

Methods In 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.

Results The 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-positiveStreptococcus pneumoniae; however, it did not have any antibacterial properties compared with azithromycin when used against Gram-negativeEscherichia coli (as a model organism) and also the respiratory pathogensPseudomonas aeruginosa and non-typeable Haemophilus influenzae. Further non-toxic Mac5 derivatives were identified with various anti-inflammatory, antiviral and antibacterial activities.

Conclusions The 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.

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