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Natamycin, an important 26-member tetraene macrolide antifungal antibiotic, is widely used as antifungal agent in the food industry and medical fields. However, low yields of the currently used production strains limit its wider applications. To improve the productivity of natamycin-producing strains, we co-expressed the Vitreoscilla hemoglobin gene vgb in Streptomyces gilvosporeus with two genes that constitute part of the natamycin biosynthesis gene cluster: pimE (encoding a signalling protein) and pimM (encoding a positive regulator). Both genes were cloned and ligated into the shuttle vector pIMEP under the control of the strong, constitutive Perm promoter, and integrated into the chromosome of S. gilvosporeus via conjugation. Natamycin production was increased 40.3% upon overexpression of pimE and pimM. Furthermore, in order to alleviate oxygen limitation, we additionally expressed vgb in the pimE and pimM over-expressing strain, yielding S. gilvosporeus/pIMEP::pimE::pimM::vgb, which showed a further 55.7% improvement for natamycin production compared to that of the recipient strain. In conclusion, co-expression of pimE and pimM with vgb led to markedly increased natamycin production, thus pointing out a potential strategy for enhancing the microbial production of other antibiotics as well. [ABSTRACT FROM AUTHOR]