Methods of and compositions for breaking down a biofilm or inhibiting, preventing or treating a microbial infection that produces a biofilm are disclosed, which involves administration of an interfering agent capable of specifically competing, titrating, or inhibiting the binding of an HU protein to a microbial DNA. By competing with HU proteins that bind to DNA scaffold in the biofilm, these interfering agents destabilize the biofilm leading to destruction and removal of the biofilm by the immune system. Further method and composition aspects are contemplated in relation to infections caused by bacteria that export an HU protein.