Identification of the chelocardin biosynthetic gene cluster from Amycolatopsis sulphurea: a platform for producing novel tetracycline antibiotics

Lukežič, Tadeja; Lešnik, Urška; Podgoršek, Ajda; Horvat, Jaka; Polak, Tomaž; Šala, Martin; Jenko, B.; Raspor, Peter; Herron, Paul; Hunter, Iain S.; Petković, Hrvoje

doi:10.1099/mic.0.070995-0

Cited by 26 publications

(41 citation statements)

References 47 publications

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“…12 Homologs of SsfL2 are found in other tetracycline biosynthetic gene clusters including OxyH in oxy pathway and DacH in dac pathway. This result led us to revisit our previous bottoms-up reconstituted oxy pathway in Streptomyces coelicolor CH999, which was reported to produce the tetracyclic product WJ83T1 (11). The involved plasmid pWJ83 was fully re-sequenced and it indeed carries a copy of oxyH, most likely as a result of the original cloning strategy (however was not reported in the manuscript).…”

Section: Resultsmentioning

confidence: 72%

An ATP-dependent ligase catalyzes the fourth ring cyclization in tetracycline biosynthesis

Raetz

Wang

et al. 2016

Tetrahedron

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a b s t r a c tCyclization steps in biosynthesis of aromatic polyketides are typically directed by specific enzymes known as cyclases. The fourth ring cyclization step that forms the fully aromatic pretetramid during tetracycline biosynthesis has not been resolved. Herein we report in vitro and in vivo studies on the fourth ring cyclization step in biosynthesis of SF2575 and related tetracyclic natural products. We demonstrate that an enzyme belonging to the ATP-dependent acyl-CoA ligase family catalyzes the C1eC18 Claisen condensation step that forms the A ring and yields the linear, tetracyclic aromatic compound that is the precursor to tetracyclic natural products. The enzyme, SsfL2, is well-conserved in all tetracycline biosynthetic gene clusters discovered to date. It is proposed that SsfL2 directly adenylates the tricyclic carboxylic acid to facilitate the final carbon-carbon bond formation, and coenzyme A is not required.

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Section: Resultsmentioning

confidence: 72%

An ATP-dependent ligase catalyzes the fourth ring cyclization in tetracycline biosynthesis

Raetz

Wang

et al. 2016

Tetrahedron

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“…However, despite its potent activity against TC-resistant pathogens, CHD did not enter the clinic. In recent years, a team led by Petković has revisited the biosynthesis of this atypical TC analogue, produced by A. sulphurea (25). By applying biosynthetic engineering approaches, they have generated CHD analogues, some of which display potent antibacterial activity against multidrug-resistant pathogens, even against Gram-negative pathogens, which today represent a great threat in hospitals; they have thus demonstrated the great potential of atypical TCs (26).…”

Section: Atypical Tetracyclinesmentioning

confidence: 99%

“…SF2575 (71), dactylocycline produced by Dactylosporangium sp. SC14051 (62), and CHD produced by A. sulphurea (25). Other structurally related tetracyclic secondary metabolites reported in the literature and produced by actinobacteria include cervimycin C produced by Streptomyces tendae HKI-179 (89), polyketomycin produced by Streptomyces diastatochromogenes Tü6028 (72) and dutomycin, isolated from the culture of Streptomyces sp.…”

Section: Future Directions In Biosynthetic Engineering Of Tetracyclinmentioning

confidence: 99%

Biosynthesis of Oxytetracycline by Streptomyces rimosus: Past, Present and Future Directions in the Development of Tetracycline Antibiotics

Petković

Lukežič²,

Šušković

2017

Food Technol. Biotechnol.

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SummaryNatural tetracycline (TC) antibiotics were the fi rst major class of therapeutics to earn the distinction of 'broad-spectrum antibiotics' and they have been used since the 1940s against a wide range of both Gram-positive and Gram-negative pathogens, mycoplasmas, intracellular chlamydiae, rickett siae and protozoan parasites. The second generation of semisynthetic tetracyclines, such as minocycline and doxycycline, with improved antimicrobial potency, were introduced during the 1960s. Despite emerging resistance to TCs erupting during the 1980s, it was not until 2006, more than four decades later, that a third--generation TC, named tigecycline, was launched. In addition, two TC analogues, omadacycline and eravacycline, developed via (semi)synthetic and fully synthetic routes, respectively, are at present under clinical evaluation. Interestingly, despite very productive early work on the isolation of a Streptomyces aureofaciens mutant strain that produced 6-demethyl-7-chlortetracycline, the key intermediate in the production of second-and third-generation TCs, biosynthetic approaches in TC development have not been productive for more than 50 years. Relatively slow and tedious molecular biology approaches for the genetic manipulation of TC-producing actinobacteria, as well as an insuffi cient understanding of the enzymatic mechanisms involved in TC biosynthesis have signifi cantly contributed to the low success of such biosynthetic engineering eff orts. However, new opportunities in TC drug development have arisen thanks to a signifi cant progress in the development of aff ordable and versatile biosynthetic engineering and synthetic biology approaches, and, importantly, to a much deeper understanding of TC biosynthesis, mostly gained over the last two decades.

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“…CHD, isolated from A. sulphurea (formerly Nocardia sulphurea ), was first described in 1962 . Its structure was subsequently established (Scheme ) . Compared to typical TCs, which have a carboxamido group at C‐2, CHD has unusual structural features, including an acetyl at C‐2, a unique aromatization pattern at ring C, and functionalization at C‐9.…”

Section: Polyketides Biosynthesis In Amycolatopsismentioning

confidence: 99%

“…In 2013, the chelocardin biosynthetic gene cluster ( chd ) was cloned from A. sulphurea ; the cluster (>20 kb) contains 18 putative ORFs and includes a type II PKS . Analysis of the cluster indicated a possible biosynthesis pathway for CHD (Scheme ).…”

Section: Polyketides Biosynthesis In Amycolatopsismentioning

confidence: 99%

Progress in Understanding the Genetic Information and Biosynthetic Pathways behind Amycolatopsis Antibiotics, with Implications for the Continued Discovery of Novel Drugs

Shen

et al. 2015

ChemBioChem

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Species of Amycolatopsis, well recognized as producers of both vancomycin and rifamycin, are also known for producing other secondary metabolites, with wide usage in medicine and agriculture. The molecular genetics of natural antibiotics produced by this genus have been well studied. Since the rise of antibiotic resistance, finding new drugs to fight infection has become an urgent priority. Progress in understanding the biosynthesis of metabolites greatly helps the rational manipulation of biosynthetic pathways, and thus to achieve the goal of generating novel natural antibiotics. The efforts made in exploiting Amycolatopsis genome sequences for the discovery of novel natural products and biosynthetic pathways are summarized.

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Identification of the chelocardin biosynthetic gene cluster from Amycolatopsis sulphurea: a platform for producing novel tetracycline antibiotics

Cited by 26 publications

References 47 publications

An ATP-dependent ligase catalyzes the fourth ring cyclization in tetracycline biosynthesis

An ATP-dependent ligase catalyzes the fourth ring cyclization in tetracycline biosynthesis

Biosynthesis of Oxytetracycline by Streptomyces rimosus: Past, Present and Future Directions in the Development of Tetracycline Antibiotics

Progress in Understanding the Genetic Information and Biosynthetic Pathways behind Amycolatopsis Antibiotics, with Implications for the Continued Discovery of Novel Drugs

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