Harnessing the intracellular triacylglycerols for titer improvement of polyketides in Streptomyces

Wang, Weishan; Li, Shanshan; Li, Zilong; Zhang, Jingyu; Fan, Keqiang; Tan, Gao-Yi; Ai, Guomin; Lam, Sin Man; Shui, Guanghou; Yang, Zhiheng; Lu, Hongzhong; Jin, Pinjiao; Li, Yihong; Chen, Xiangyin; Xia, Xuekui; Liu, Xueting; Dannelly, H. Kathleen; Yang, Chen; Yang, Yi; Zhang, Siliang; Alterovitz, Gil; Xiang, Wensheng; Zhang, Lixin

doi:10.1038/s41587-019-0335-4

Cited by 127 publications

(109 citation statements)

References 51 publications

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“…A putative link between TAG content and antibiotic activity was already anticipated twenty years ago by Olukoshi and Packter [14,15] in S. lividans. Furthermore, the impaired biosynthesis [16,17] or enhanced degradation [18][19][20] of fatty acids was indeed shown to be correlated with increased antibiotic biosynthesis in S. coelicolor. Similarly, enhanced spiramycin biosynthesis was correlated with lower lipid content in S. ambofaciens [21].…”

Section: Introductionmentioning

confidence: 89%

Negative Correlation between Lipid Content and Antibiotic Activity in Streptomyces: General Rule and Exceptions

et al. 2020

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Streptomycetes are well known antibiotic producers and are among the rare prokaryotes able to store carbon as lipids. Previous comparative studies of the weak antibiotic producer Streptomyces lividans with its ppk mutant and with Streptomyces coelicolor, which both produce antibiotics, suggested the existence of a negative correlation between total lipid content and the ability to produce antibiotics. To determine whether such a negative correlation can be generalized to other Streptomyces species, fifty-four strains were picked randomly and grown on modified R2YE medium, limited in phosphate, with glucose or glycerol as the main carbon source. The total lipid content and antibiotic activity against Micrococcus luteus were assessed for each strain. This study revealed that the ability to accumulate lipids was not evenly distributed among strains and that glycerol was more lipogenic than glucose and had a negative impact on antibiotic biosynthesis. Furthermore, a statistically significant negative Pearson correlation between lipid content and antibiotic activity could be established for most strains, but a few strains escape this general law. These exceptions are likely due to limits and biases linked to the type of test used to determine antibiotic activity, which relies exclusively on Micrococcus luteus sensitivity. They are characterized either by high lipid content and high antibiotic activity or by low lipid content and undetectable antibiotic activity against Micrococcus luteus. Lastly, the comparative genomic analysis of two strains with contrasting lipid content, and both named Streptomyces antibioticus (DSM 41,481 and DSM 40,868, which we found to be phylogenetically related to Streptomyces lavenduligriseus), indicated that some genetic differences in various pathways related to the generation/consumption of acetylCoA could be responsible for such a difference.

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Section: Introductionmentioning

confidence: 89%

Negative Correlation between Lipid Content and Antibiotic Activity in Streptomyces: General Rule and Exceptions

et al. 2020

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“…Inadequate sugar utilization efficiency is a general knotty issue hindering further titer and yield improvement of desired products [ 25 , 42 ]. Especially in Streptomyces fermentations, sugar uptake capability is significantly reduced during secondary metabolite biosynthetic period [ 4 ]. Considering the significant contribution of sugar uptake transporter to the flux towards products, it is quite important to investigate sugar uptake transporters first [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

“…Biosynthesis of secondary metabolites in Streptomyces occurs in stationary phase, when cell growth is almost stopped [ 1 , 2 ]. Despite the soluble sugars are widely used as main carbon source for both cell growth and secondary metabolite biosynthesis, they are primarily consumed during growth period rather than the stationary phase [ 3 , 4 ]. When entering stationary phase, a phenomenon of dramatic decrease of sugar uptake rate is usually observed in Streptomyces fermentations [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

“…However, the present titer and yield of milbemycins in S. bingchenggensis are much lower compared to the well-exploited biopesticide avermectin B 1a . By long-term and collective efforts from scientists and engineers from both academic and manufacturers, the titer of avermectin B 1a in the producing Streptomyces avermitilis has elevated from 0.009 g/L up to more than 9 g/L, and the price has decreased to less than 500 RMB/kg [ 4 , [21] , [22] , [23] , [24] ]. Despite milbemycins show more potential than avermectins in plant protection, the current production cost still hinders the widespread applications in the agricultural field.…”

Section: Introductionmentioning

confidence: 99%

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Mining and fine-tuning sugar uptake system for titer improvement of milbemycins in Streptomyces bingchenggensis

Jin

Zhang

et al. 2020

Synthetic and Systems Biotechnology

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Dramatic decrease of sugar uptake is a general phenomenon in Streptomyces at stationary phase, when antibiotics are extensively produced. Milbemycins produced by Streptomyces bingchenggensis are a group of valuable macrolide biopesticides, while the low yield and titer impede their broad applications in agricultural field. Considering that inadequate sugar uptake generally hinders titer improvement of desired products, we mined the underlying sugar uptake systems and fine-tuned their expression in this work. First, we screened the candidates at both genomic and transcriptomic level in S. bingchenggensis . Then, two ATP-binding cassette transporters named TP2 and TP5 were characterized to improve milbemycin titer and yield significantly. Next, the appropriate native temporal promoters were selected and used to tune the expression of TP2 and TP5, resulting in a maximal milbemycin A3/A4 titer increase by 36.9% to 3321 mg/L. Finally, TP2 and TP5 were broadly fine-tuned in another two macrolide biopesticide producers Streptomyces avermitilis and Streptomyces cyaneogriseus , leading to a maximal titer improvement of 34.1% and 52.6% for avermectin B 1a and nemadectin, respectively. This work provides useful transporter tools and corresponding engineering strategy for Streptomyces .

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“…As such, the cellular redox status is closely linked to the secondary metabolism. For example, inhibition of three enzymes in the TCA cycle by NADH resulted in a decrease of the carbon flux toward the TCA cycle and prompted polyketides production in streptomycetes (Wang et al, 2020). On the other hand, a higher carbon flux through the TCA cycle contributed to enhance the accumulation of precursors for erythromycin (Hong et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

The Expression of NOX From Synthetic Promoters Reveals an Important Role of the Redox Status in Regulating Secondary Metabolism of Saccharopolyspora erythraea

Chu

Jensen

2020

Front. Bioeng. Biotechnol.

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Redox cofactors play a pivotal role in primary cellular metabolism, whereas the clear link between redox status and secondary metabolism is still vague. In this study we investigated effects of redox perturbation on the production of erythromycin in Saccharopolyspora erythraea by expressing the water-forming NADH oxidase (NOX) from Streptococcus pneumonia at different levels with synthetic promoters. The expression of NOX reduced the intracellular [NADH]/[NAD + ] ratio significantly in S. erythraea which resulted in an increased production of erythromycin by 19∼29% and this increment rose to 60% as more oxygen was supplied. In contrast, the lower redox ratio resulted in a decreased production of another secondary metabolite, the reddish pigment 7-O-rahmnosyl flaviolin. The metabolic shifts of secondary metabolism results in a higher NADH availability which compensates for its oxidization via NOX. The expression of the erythromycin biosynthesis gene cluster (BGC) in the NOXexpression strains was upregulated as the activity of diguanylate cyclase was inhibited moderately by NADH. This study also suggested that lower intracellular [NADH]/[NAD + ] ratio benefits the biosynthesis of erythromycin by potentially affecting the biosynthesis of the secondary messenger, bis-(3-5)-cyclic dimeric guanosine monophosphate (c-di-GMP), which may stimulate the positive regulation of erythromycin BGC via BldD. The present work provides a basis for future cofactor manipulation in S. erythraea to improve the industrial production of erythromycin.

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Harnessing the intracellular triacylglycerols for titer improvement of polyketides in Streptomyces

Cited by 127 publications

References 51 publications

Negative Correlation between Lipid Content and Antibiotic Activity in Streptomyces: General Rule and Exceptions

Negative Correlation between Lipid Content and Antibiotic Activity in Streptomyces: General Rule and Exceptions

Mining and fine-tuning sugar uptake system for titer improvement of milbemycins in Streptomyces bingchenggensis

The Expression of NOX From Synthetic Promoters Reveals an Important Role of the Redox Status in Regulating Secondary Metabolism of Saccharopolyspora erythraea

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