The biosynthesis of the Streptomyces antibiotic bicyclomycin

Bradley, Emma; Herbert, Richard B.; Lawrie, K. W. M.; Khan, Jeffrey A.; Moody, Claire M.; Young, Douglas W.

doi:10.1016/0040-4039(96)01521-3

Cited by 13 publications

(11 citation statements)

References 11 publications

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“…Published feeding experiments indicate that BCM is a DKP derived from l -leucine and l -isoleucine and that a cytochrome P450 is likely to be involved in the pathway ( 13 ). Furthermore, a number of additional oxidative reactions are needed to form the final molecule ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In contrast with the extensive knowledge on BCM's mechanism of action ( 6 , 7 ), very little was known about the biosynthesis of this antibiotic. Feeding experiments previously showed that the DKP scaffold derives from l -leucine and l -isoleucine, as well as the likely involvement of a cytochrome P450 monooxygenase in one of the oxidative steps that convert cIL into BCM ( 13 ) ( Fig. 1A ).…”

Section: Introductionmentioning

confidence: 89%

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Discovery and Biosynthesis of the Antibiotic Bicyclomycin in Distantly Related Bacterial Classes

Vior

Lacret

Chandra

et al. 2018

Appl Environ Microbiol

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Bicyclomycin (BCM) is a clinically promising antibiotic that is biosynthesized by Streptomyces cinnamoneus DSM 41675. BCM is structurally characterized by a core cyclo(l-Ile-l-Leu) 2,5-diketopiperazine (DKP) that is extensively oxidized. Here, we identify the BCM biosynthetic gene cluster, which shows that the core of BCM is biosynthesized by a cyclodipeptide synthase, and the oxidative modifications are introduced by five 2-oxoglutarate-dependent dioxygenases and one cytochrome P450 monooxygenase. The discovery of the gene cluster enabled the identification of BCM pathways encoded by the genomes of hundreds of Pseudomonas aeruginosa isolates distributed globally, and heterologous expression of the pathway from P. aeruginosa SCV20265 demonstrated that the product is chemically identical to BCM produced by S. cinnamoneus. Overall, putative BCM gene clusters have been found in at least seven genera spanning Actinobacteria and Proteobacteria (Alphaproteobacteria, Betaproteobacteria, and Gammaproteobacteria). This represents a rare example of horizontal gene transfer of an intact biosynthetic gene cluster across such distantly related bacteria, and we show that these gene clusters are almost always associated with mobile genetic elements.IMPORTANCE Bicyclomycin is the only natural product antibiotic that selectively inhibits the transcription termination factor Rho. This mechanism of action, combined with its proven biological safety and its activity against clinically relevant Gram-negative bacterial pathogens, makes it a very promising antibiotic candidate. Here, we report the identification of the bicyclomycin biosynthetic gene cluster in the known bicyclomycin-producing organism Streptomyces cinnamoneus, which will enable the engineered production of new bicyclomycin derivatives. The identification of this gene cluster also led to the discovery of hundreds of bicyclomycin pathways encoded in highly diverse bacteria, including in the opportunistic pathogen Pseudomonas aeruginosa. This wide distribution of a complex biosynthetic pathway is very unusual and provides an insight into how a pathway for an antibiotic can be transferred between diverse bacteria.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 89%

Discovery and Biosynthesis of the Antibiotic Bicyclomycin in Distantly Related Bacterial Classes

Vior

Lacret

Chandra

et al. 2018

Appl Environ Microbiol

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show abstract

“…These products could be intermediates in bicyclomycin biosynthesis, as previously detected by Bradley et al . for intermediates 2 and 3 10 or shunt products resulting from the promiscuous activity of some tailoring enzymes on substrate analogues that accumulate in the absence of proper metabolic flux. Some of these products were also detected in trace amounts by LC/MS analysis in the culture supernatants of S. cinnamoneus Δbcm::aphII harbouring an intact copy of the bcm BGC.…”

Section: Resultsmentioning

confidence: 99%

“…In bacteria, the synthesis of the DKP core can be catalysed either by nonribosomal peptide synthetases (NRPSs) or by cyclodipeptide synthases (CDPSs) 9 . At the outset of our investigation into the biosynthesis of bicyclomycin only the first and last intermediate were proposed: cyclo-( l -isoleucyl- l -leucyl) (cIL) ( 2 ) and dihydrobicyclomycin ( 3 ), respectively 10 . During the final steps of our work, which focused on S. cinnamoneus , several studies on bicyclomycin biosynthesis that used in vitro approaches or heterologous expression were published, identifying biosynthetic genes and proposing a biosynthetic pathway for bicyclomycin in both Actinobacteria and Proteobacteria 11–13 .…”

Section: Introductionmentioning

confidence: 99%

Study of bicyclomycin biosynthesis in Streptomyces cinnamoneus by genetic and biochemical approaches

Witwinowski

Moutiez

Coupet

et al. 2019

Sci Rep

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The 2,5-Diketopiperazines (DKPs) constitute a large family of natural products with important biological activities. Bicyclomycin is a clinically-relevant DKP antibiotic that is the first and only member in a class known to target the bacterial transcription termination factor Rho. It derives from cyclo-(l-isoleucyl-l-leucyl) and has an unusual and highly oxidized bicyclic structure that is formed by an ether bridge between the hydroxylated terminal carbon atom of the isoleucine lateral chain and the alpha carbon of the leucine in the diketopiperazine ring. Here, we paired in vivo and in vitro studies to complete the characterization of the bicyclomycin biosynthetic gene cluster. The construction of in-frame deletion mutants in the biosynthetic gene cluster allowed for the accumulation and identification of biosynthetic intermediates. The identity of the intermediates, which were reproduced in vitro using purified enzymes, allowed us to characterize the pathway and corroborate previous reports. Finally, we show that the putative antibiotic transporter was dispensable for the producing strain.

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“…1B). A gene-implied enzyme inhibition (GIEI) strategy, derived from the hypothesis-based enzyme modulation described elsewhere (19,20), was introduced to identify the key diversification steps for the PS reactionderived compounds (Figs. 2-4).…”

mentioning

confidence: 99%

Pictet–Spengler reaction-based biosynthetic machinery in fungi

Yan

Gang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The Pictet-Spengler (PS) reaction constructs plant alkaloids such as morphine and camptothecin, but it has not yet been noticed in the fungal kingdom. Here, a silent fungal Pictet-Spenglerase (FPS) gene of Chaetomium globosum 1C51 residing in Epinephelus drummondhayi guts is described and ascertained to be activable by 1-methyl-Ltryptophan (1-MT). The activated FPS expression enables the PS reaction between 1-MT and flavipin (fungal aldehyde) to form "unnatural" natural products with unprecedented skeletons, of which chaetoglines B and F are potently antibacterial with the latter inhibiting acetylcholinesterase. A gene-implied enzyme inhibition (GIEI) strategy has been introduced to address the key steps for PS product diversifications. In aggregation, the work designs and validates an innovative approach that can activate the PS reaction-based fungal biosynthetic machinery to produce unpredictable compounds of unusual and novel structure valuable for new biology and biomedicine.Pictet-Spengler reaction | FPS | Chaetomium globosum 1C51 | GIEI

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The biosynthesis of the Streptomyces antibiotic bicyclomycin

Cited by 13 publications

References 11 publications

Discovery and Biosynthesis of the Antibiotic Bicyclomycin in Distantly Related Bacterial Classes

Discovery and Biosynthesis of the Antibiotic Bicyclomycin in Distantly Related Bacterial Classes

Study of bicyclomycin biosynthesis in Streptomyces cinnamoneus by genetic and biochemical approaches

Pictet–Spengler reaction-based biosynthetic machinery in fungi

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