Kinetics of rapamycin production by Streptomyces hygroscopicus MTCC 4003

Dutta, Subhasish; Basak, Bikram; Bhunia, Biswanath; Chakraborty, Samayita; Dey, Apurba

doi:10.1007/s13205-013-0189-2

Cited by 18 publications

(17 citation statements)

References 33 publications

(52 reference statements)

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“…The rapamycin titers of S. rapamycinicus , particularly high-yield engineered strains, decreased sharply in the late fermentation stages (on day 11) (Figure 2 – 6 ). Similar phenomena were reported previously ( 50 , 51 ) and are likely to be ascribed to rapamycin degradation ( 51 ). The detailed mechanism for this phenomenon remains elusive.…”

Section: Discussionsupporting

confidence: 91%

Developing an endogenous quorum-sensing based CRISPRi circuit for autonomous and tunable dynamic regulation of multiple targets in Streptomyces

Tian

Yang

et al. 2020

Nucleic Acids Research

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Quorum-sensing (QS) mediated dynamic regulation has emerged as an effective strategy for optimizing product titers in microbes. However, these QS-based circuits are often created on heterologous systems and require careful tuning via a tedious testing/optimization process. This hampers their application in industrial microbes. Here, we design a novel QS circuit by directly integrating an endogenous QS system with CRISPRi (named EQCi) in the industrial rapamycin-producing strain Streptomyces rapamycinicus. EQCi combines the advantages of both the QS system and CRISPRi to enable tunable, autonomous, and dynamic regulation of multiple targets simultaneously. Using EQCi, we separately downregulate three key nodes in essential pathways to divert metabolic flux towards rapamycin biosynthesis and significantly increase its titers. Further application of EQCi to simultaneously regulate these three key nodes with fine-tuned repression strength boosts the rapamycin titer by ∼660%, achieving the highest reported titer (1836 ± 191 mg/l). Notably, compared to static engineering strategies, which result in growth arrest and suboptimal rapamycin titers, EQCi-based regulation substantially promotes rapamycin titers without affecting cell growth, indicating that it can achieve a trade-off between essential pathways and product synthesis. Collectively, this study provides a convenient and effective strategy for strain improvement and shows potential for application in other industrial microorganisms.

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Section: Discussionsupporting

confidence: 91%

Developing an endogenous quorum-sensing based CRISPRi circuit for autonomous and tunable dynamic regulation of multiple targets in Streptomyces

Tian

Yang

et al. 2020

Nucleic Acids Research

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“…Some examples of polyketides produced by Streptomyces are rapamycin (produced by Streptomyces hygroscopicus ), oleandomycin (produced by Streptomyces antibioticus ), actinorhodin (produced by Streptomyces coelicolor A3(2)), daunorubicin (produced by Streptomyces peucetius ) and caprazamycin (produced by Streptomyces sp. MK730-62F2) [19,20,21,22,23].…”

Section: Introductionmentioning

confidence: 99%

Biosynthesis of Polyketides in Streptomyces

2019

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Polyketides are a large group of secondary metabolites that have notable variety in their structure and function. Polyketides exhibit a wide range of bioactivities such as antibacterial, antifungal, anticancer, antiviral, immune-suppressing, anti-cholesterol, and anti-inflammatory activity. Naturally, they are found in bacteria, fungi, plants, protists, insects, mollusks, and sponges. Streptomyces is a genus of Gram-positive bacteria that has a filamentous form like fungi. This genus is best known as one of the polyketides producers. Some examples of polyketides produced by Streptomyces are rapamycin, oleandomycin, actinorhodin, daunorubicin, and caprazamycin. Biosynthesis of polyketides involves a group of enzyme activities called polyketide synthases (PKSs). There are three types of PKSs (type I, type II, and type III) in Streptomyces responsible for producing polyketides. This paper focuses on the biosynthesis of polyketides in Streptomyces with three structurally-different types of PKSs.

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“…This system holds many of the features required for clinical use. First, rapamycin is a clinically approved drug, used as an antifungal and antitumor molecule that can be administered orally and can cross the BBB (Dutta et al, 2014). Second, the system ensures low basal expression of the transgene in the absence of rapamycin, but can be triggering by low doses of the drug (Naidoo and Young, 2012).…”

Section: Regulation Of Gene Expressionmentioning

confidence: 99%

Gene Therapy Tools for Brain Diseases

et al. 2019

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Neurological disorders affecting the central nervous system (CNS) are still incompletely understood. Many of these disorders lack a cure and are seeking more specific and effective treatments. In fact, in spite of advancements in knowledge of the CNS function, the treatment of neurological disorders with modern medical and surgical approaches remains difficult for many reasons, such as the complexity of the CNS, the limited regenerative capacity of the tissue, and the difficulty in conveying conventional drugs to the organ due to the blood–brain barrier. Gene therapy, allowing the delivery of genetic materials that encodes potential therapeutic molecules, represents an attractive option. Gene therapy can result in a stable or inducible expression of transgene(s), and can allow a nearly specific expression in target cells. In this review, we will discuss the most commonly used tools for the delivery of genetic material in the CNS, including viral and non-viral vectors; their main applications; their advantages and disadvantages. We will discuss mechanisms of genetic regulation through cell-specific and inducible promoters, which allow to express gene products only in specific cells and to control their transcriptional activation. In addition, we will describe the applications to CNS diseases of post-transcriptional regulation systems (RNA interference); of systems allowing spatial or temporal control of expression [optogenetics and Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)]; and of gene editing technologies (CRISPR/Cas9, Zinc finger proteins). Particular attention will be reserved to viral vectors derived from herpes simplex type 1, a potential tool for the delivery and expression of multiple transgene cassettes simultaneously.

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Kinetics of rapamycin production by Streptomyces hygroscopicus MTCC 4003

Cited by 18 publications

References 33 publications

Developing an endogenous quorum-sensing based CRISPRi circuit for autonomous and tunable dynamic regulation of multiple targets in Streptomyces

Developing an endogenous quorum-sensing based CRISPRi circuit for autonomous and tunable dynamic regulation of multiple targets in Streptomyces

Biosynthesis of Polyketides in Streptomyces

Gene Therapy Tools for Brain Diseases

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