Symbionts in sponges must interact with the host immune system, and this can be mediated by immunomodulators. As the bases of the immune system in sponges resemble those of higher metazoans, it is possible that compounds from this microbiota show similar effects in other phyla. It is also known that several antibiotics, in special macrolides, can modulate many components of the immune response and sponges and their associated microorganisms are a rich source of these compounds. Therefore, we tested the immunosuppressive capacity of antibiotic substances produced by bacterial and fungal strains isolated from the Amazon freshwater sponge Metania reticulata. Fourteen bacterial and six fungal strains were obtained from samples of M. reticulata collected in the Negro River (Amazon Central Basin region), during the dry season. These cultures were monitored for natural antimicrobial activity, and two Bacillus strains (MERETb.761 and MERETb.762) and one fungus (MERETf.010) were selected. One Bacillus strain, MERETb.762, showed strong and specific antibiosis on Staphylococcus aureus and two fractions of its extract inhibited the degranulation of RBL–2H3 cells. The predicted formulas of these fractions were C12H6N4O8 and C25H4N2O6, both corresponding to nitroaromatic compounds.