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

J Antimicrob Chemother. 2016 Oct;71(10):2767-81. doi: 10.1093/jac/dkw222. Epub 2016 Jul 25.


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-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.

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.

MeSH terms

  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / isolation & purification
  • Anti-Bacterial Agents / pharmacology*
  • Anti-Bacterial Agents / therapeutic use
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / isolation & purification
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
  • Antiviral Agents / chemistry*
  • Antiviral Agents / isolation & purification
  • Antiviral Agents / pharmacology*
  • Antiviral Agents / therapeutic use
  • Asthma / drug therapy
  • Bronchi / cytology
  • Bronchi / drug effects
  • Cells, Cultured
  • Drug Discovery*
  • Drug Evaluation, Preclinical
  • Epithelial Cells / drug effects
  • Escherichia coli / drug effects
  • Gram-Negative Bacteria / drug effects
  • Gram-Positive Bacteria / drug effects
  • Haemophilus influenzae / drug effects
  • Humans
  • Interferon-beta / immunology
  • Interferons / biosynthesis
  • Interferons / immunology*
  • Interleukin-6 / immunology
  • Interleukin-6 / metabolism
  • Interleukin-8 / immunology
  • Interleukin-8 / metabolism
  • Macrolides / chemistry
  • Macrolides / pharmacology*
  • Macrolides / therapeutic use
  • Myxovirus Resistance Proteins / genetics
  • Oxidoreductases Acting on CH-CH Group Donors
  • Proteins / genetics
  • Pseudomonas aeruginosa / drug effects
  • Rhinovirus / drug effects
  • Virus Replication / drug effects


  • Anti-Bacterial Agents
  • Anti-Inflammatory Agents, Non-Steroidal
  • Antiviral Agents
  • Interleukin-6
  • Interleukin-8
  • MX1 protein, human
  • Macrolides
  • Myxovirus Resistance Proteins
  • Proteins
  • Interferon-beta
  • Interferons
  • Oxidoreductases Acting on CH-CH Group Donors
  • RSAD2 protein, human