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The <jats:italic>mtrA<\/jats:italic> (<jats:italic>sav_5063<\/jats:italic>) gene functions as a transcriptional regulator belonging to the OmpR family. As a pleiotropic regulator, <jats:italic>mtrA<\/jats:italic> not only influences the growth, development, and morphological differentiation of strains but also modulates genes associated with primary metabolism. However, the regulatory role of MtrA in avermectin biosynthesis remains to be elucidated.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>In this study, we demonstrated that MtrA, a novel OmpR-family transcriptional regulator in <jats:italic>S. avermitilis<\/jats:italic>, exerts global regulator effects by negatively regulating avermectin biosynthesis and cell growth while positively controlling morphological differentiation. The deletion of the <jats:italic>mtrA<\/jats:italic> gene resulted in an increase in avermectin production, accompanied by a reduction in biomass and a delay in the formation of aerial hyphae and spores. The Electrophoretic Mobility Shift Assay (EMSA) revealed that MtrA exhibited binding affinity towards the upstream region of <jats:italic>aveR<\/jats:italic>, the intergenic region between <jats:italic>aveA1<\/jats:italic> and <jats:italic>aveA2<\/jats:italic> genes, as well as the upstream region of <jats:italic>aveBVIII<\/jats:italic> in vitro. These findings suggest that MtrA exerts a negative regulatory effect on avermectin biosynthesis by modulating the expression of avermectin biosynthesis cluster genes. Transcriptome sequencing and fluorescence quantitative PCR analysis showed that <jats:italic>mtrA<\/jats:italic> deletion increased the transcript levels of the cluster genes <jats:italic>aveR<\/jats:italic>, <jats:italic>aveA1<\/jats:italic>, <jats:italic>aveA2<\/jats:italic>, <jats:italic>aveC<\/jats:italic>, <jats:italic>aveE<\/jats:italic>, <jats:italic>aveA4<\/jats:italic> and <jats:italic>orf-1<\/jats:italic>, which explains the observed increase in avermectin production in the knockout strain. Furthermore, our findings demonstrate that MtrA positively regulates the cell division and differentiation genes <jats:italic>bldM<\/jats:italic> and <jats:italic>ssgC<\/jats:italic>, while exerting a negative regulatory effect on <jats:italic>bldD<\/jats:italic>, thereby modulating the primary metabolic processes associated with cell division, differentiation and growth in <jats:italic>S. avermitilis<\/jats:italic>, consequently impacting avermectin biosynthesis.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>In this study, we investigated the negative regulatory effect of the global regulator MtrA on avermectin biosynthesis and its effects on morphological differentiation and cell growth, and elucidated its transcriptional regulatory mechanism. Our findings indicate that MtrA plays crucial roles not only in the biosynthesis of avermectin but also in coordinating intricate physiological processes in <jats:italic>S. avermitilis.<\/jats:italic> These findings provide insights into the synthesis of avermectin and shed light on the primary and secondary metabolism of <jats:italic>S. avermitilis<\/jats:italic> mediated by OmpR-family regulators.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12934-024-02331-2","type":"journal-article","created":{"date-parts":[[2024,4,8]],"date-time":"2024-04-08T02:06:12Z","timestamp":1712541972000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Characterization of a pleiotropic regulator MtrA in Streptomyces avermitilis controlling avermectin production and morphological differentiation"],"prefix":"10.1186","volume":"23","author":[{"given":"Jinpin","family":"Tian","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanbo","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianyu","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyu","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,8]]},"reference":[{"key":"2331_CR1","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1128\/AAC.15.3.368","volume":"15","author":"TW Miller","year":"1979","unstructured":"Miller TW, Chaiet L, Cole DJ, Cole LJ, Flor JE, Goegelman RT, Gullo VP, Joshua H, Kempf AJ, Krellwitz WR, et al. 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