The Fourth Affiliated Hospital & Institute of Pharmaceutical Biotechnology, School of Medicine, Zhejiang University, Hangzhou, China.
School of Biology, Food and Environment, Hefei University, Hefei, China.
Microb Biotechnol. 2024 Oct;17(10):e70023. doi: 10.1111/1751-7915.70023.
Streptomyces genus produces a large number of antibiotics, which are always synthesized by specific biosynthetic gene clusters (BGCs). To resist autotoxicity, transporters encoded by genes located within BGC occasionally pump antibiotic along with transporter encoded by gene located outside BGC. Daunorubicin is an anthracycline antibiotic biosynthesized by Streptomyces species, playing a crucial role in the treatment of leukaemia. In existing studies, only one two-component ATP-binding cassette (ABC) transporter, encoded by drrA1-drrB1 (abbreviated as drrAB1) and located within the daunorubicin BGC, has been proven to extrude daunorubicin. In this work, two other two-component ABC transporters, encoded by drrAB2 and drrAB3 and located outside the cluster, were found to play the complementary role in daunorubicin efflux in S. coeruleorubidus. Disruption of three drrABs resulted in a 94% decrease in daunorubicin production. Furthermore, drrAB2 is regulated by the TetR family regulator DrrR1, responding to the intracellular accumulation of daunorubicin and suggesting its role in stress response and self-resistance. Although the homologues of DrrAB1 are only found in three anthracycline BGCs, the homologues of DrrAB2 and DrrAB3 are spread in many Streptomyces strains which do not contain any known anthracycline BGC. This indicates that DrrAB2 and DrrAB3 may recognize and extrude a broader range of substrates besides daunorubicin, thus playing a more extensive role in cellular detoxification.
链霉菌属产生大量抗生素，这些抗生素通常由特定的生物合成基因簇 (BGCs) 合成。为了抵抗自毒性，位于 BGC 内的基因编码的转运蛋白偶尔会与位于 BGC 外的基因编码的转运蛋白一起将抗生素泵出。柔红霉素是一种由链霉菌属合成的蒽环类抗生素，在治疗白血病方面发挥着至关重要的作用。在现有研究中，仅证明了一种由 drrA1-drrB1（简称 drrAB1）编码的二组分 ATP 结合盒 (ABC) 转运蛋白位于柔红霉素 BGC 内，可将柔红霉素排出细胞外。在这项工作中，发现了另外两种位于簇外的二组分 ABC 转运蛋白 drrAB2 和 drrAB3，它们在 S. coeruleorubidus 中发挥柔红霉素外排的互补作用。敲除三个 drrAB 导致柔红霉素产量降低了 94%。此外，drrAB2 受 TetR 家族调节剂 DrrR1 调控，响应柔红霉素的细胞内积累，表明其在应激反应和自我抗性中的作用。尽管 drrAB1 的同源物仅在三个蒽环类 BGC 中发现，但 drrAB2 和 drrAB3 的同源物广泛分布在许多不含有任何已知蒽环类 BGC 的链霉菌株中。这表明 DrrAB2 和 DrrAB3 可能识别并排出除柔红霉素以外的更广泛的底物，从而在细胞解毒中发挥更广泛的作用。
