Inhibition of influenza virus replication by macrolide antibiotics

The threat of an influenza pandemic is constantly with us. The spread of bird flu across the world has heightened concerns about pandemic risk. This proposal is concerned with the development of drugs that will inhibit influenza virus growth and thereby prevent or reduce the severity of the associated illness. Our study will attempt to define the way in which these drugs work against flu. This information will be useful in improving our understanding of the influenza virus. It may also help us to develop better drugs in the future. The control of bird flu may be crucial in reducing the risk of a human pandemic; antiviral drugs may have a role in this. New flu drugs that can be used in humans will clearly be useful when a human pandemic next occurs.

The threat of a new influenza virus pandemic makes the development of new anti-influenza agents a priority. We have observed that certain macrolide antibiotics already licensed for use in poultry and swine inhibit the in vitro replication of influenza A virus strains at sub micromolar concentrations. Amongst these Aivlosin, (3-acetyl-4 -isovaleryl tylosin tartrate), is particularly promising given its low toxicity and rapid concentration in epithelia. Given the potential benefits to be gained from the identification of an antiviral activity for a licensed antimicrobial that is available in tonne quantities at relatively low cost, we think it is justified to pursue further studies aimed at characterising the effects of macrolides on influenza virus infection. We will investigate the mechanism of inhibition by Aivlosin and related compounds in vitro. The issues to be addressed will include the effects of the drugs on a range of key influenza strains in a variety of cell types, the putative antiviral effects of related compounds, the mechanism(s) of antiviral action, the potential for emergence of resistant mutants and finally their interactions with adamantanes. This proposal has potential implications for pandemic intervention strategies at both the animal and human levels.