Filamentous fungi encode an untapped reservoir of natural products whose biosynthesis enzymes are often encoded by gene clusters. The majority of these gene clusters are only activated under distinct environmental conditions such as the presence of distinct neighbouring microorganisms but not under standard laboratory conditions. Previously, we provided evidence for such a scenario with the specific activation of the silent ors gene cluster in the filamentous fungus Aspergillus nidulans by the bacterium Streptomyces rapamycinicus. The bacterium triggered the activation of the GcnE histone acetyltransferase that acetylated histone 3 in nucleosomes of the ors gene cluster and the basR transcription factor, and thereby the gene cluster. The inducing compound was shown to be the bacterial arginoketide azalomycin F. Here, by inhibitor studies with the pan-sirtuin inhibitor nicotinamide (NAM) the involvement of a sirtuin HDAC was implied. Accordingly, deletion of all six putative sirtuin-encoding genes (sirA-E and hstA) revealed that only deletion of sirE led to production of orsellinic acid by A. nidulans without the need of the bacterium. Also other effects on growth and colony morphology due to NAM were phenocopied by the sirE deletion mutant. Addition of NAM did not compensate for the loss of the BasR transcription factor required for activation of the ors gene cluster. Collectively, SirE is the negative regulator of the bacteria-induced activation of the ors BGC. In line, addition of NAM to monocultures of Aspergillus mulundensis encoding a sirtuin E with highest similarity to the A. nidulans protein also activated the ors BGC in this fungus.