The involvement of multiple ABC transporters in daunorubicin efflux in Streptomyces coeruleorubidus

IF 5.7 2区 生物学
Jianxin Dong, Jiali Ning, Yu Tian, Han Li, Hua Chen, Wenjun Guan
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Abstract

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.

Abstract Image

Abstract Image

多种 ABC 转运体参与了柯氏链霉菌中多柔比星的外排。
链霉菌属生产大量抗生素,这些抗生素总是由特定的生物合成基因簇(BGC)合成。为了抵抗自体毒性,位于 BGC 内的基因编码的转运体偶尔会与位于 BGC 外的基因编码的转运体一起泵送抗生素。多柔比星是一种由链霉菌生物合成的蒽环类抗生素,在治疗白血病方面发挥着重要作用。在现有的研究中,只有一个由 drrrA1-drrB1 (缩写为 drrrAB1)编码的双组分 ATP 结合盒(ABC)转运体能挤出多柔比星 BGC。在这项研究中,我们发现由 drrAB2 和 drrAB3 编码的另外两个双组分 ABC 转运体(位于簇外)在 S. coeruleorubidus 的多柔比星外排过程中发挥着互补作用。破坏三个 drrABs 会导致达乌鲁比星产量减少 94%。此外,drrAB2 受 TetR 家族调节因子 DrrrR1 的调控,对细胞内达乌鲁比星的积累做出反应,表明其在应激反应和自我抵抗中的作用。虽然 DrrAB1 的同源物只存在于三个蒽环类 BGC 中,但 DrrAB2 和 DrrAB3 的同源物却分布在许多不含任何已知蒽环类 BGC 的链霉菌株中。这表明 DrrAB2 和 DrrAB3 除了能识别和挤出达柔比星外,还能识别和挤出更广泛的底物,从而在细胞解毒过程中发挥更广泛的作用。
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来源期刊
Microbial Biotechnology
Microbial Biotechnology Immunology and Microbiology-Applied Microbiology and Biotechnology
CiteScore
11.20
自引率
3.50%
发文量
162
审稿时长
1 months
期刊介绍: Microbial Biotechnology publishes papers of original research reporting significant advances in any aspect of microbial applications, including, but not limited to biotechnologies related to: Green chemistry; Primary metabolites; Food, beverages and supplements; Secondary metabolites and natural products; Pharmaceuticals; Diagnostics; Agriculture; Bioenergy; Biomining, including oil recovery and processing; Bioremediation; Biopolymers, biomaterials; Bionanotechnology; Biosurfactants and bioemulsifiers; Compatible solutes and bioprotectants; Biosensors, monitoring systems, quantitative microbial risk assessment; Technology development; Protein engineering; Functional genomics; Metabolic engineering; Metabolic design; Systems analysis, modelling; Process engineering; Biologically-based analytical methods; Microbially-based strategies in public health; Microbially-based strategies to influence global processes
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