A novel chemical communication between Streptomyces rapamycinicus and Aspergillus nidulans requires the bacterium-produced polaramycin B, not physical contact, for orsellinic acid (ORS) production in the fungus. This study shows that the macrolide polaramycin B triggers ORS production without direct contact, together with other secondary metabolites, leading to down regulation of fungal genes involved in membrane stability and metabolism, while upregulating genes for ribosome biogenesis and cellular defence.