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Keywords:

  • agriculture;
  • pathogenesis;
  • plant diseases;
  • streptomycetes;
  • toxins

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Thaxtomins
  5. Biological activity of thaxtomins
  6. Biosynthesis of the thaxtomin phytotoxins
  7. Regulation of thaxtomin biosynthesis
  8. Concanamycins
  9. COR-like metabolites
  10. Bioactivity of the S. scabies COR-like metabolite
  11. Regulation of COR-like metabolite production in S. scabies
  12. FD-891
  13. Borrelidin
  14. Concluding remarks
  15. Acknowledgements
  16. Conflict of interest
  17. References
  18. Supporting Information

Streptomyces is a large genus consisting of soil-dwelling, filamentous bacteria that are best known for their capability of producing a vast array of medically and agriculturally useful secondary metabolites. In addition, a small number of Streptomyces spp. are capable of colonizing and infecting the underground portions of living plants and causing economically important crop diseases such as potato common scab (CS). Research into the mechanisms of Streptomyces plant pathogenicity has led to the identification and characterization of several phytotoxic secondary metabolites that are known or suspected of contributing to diseases in various plants. The best characterized are the thaxtomin phytotoxins, which play a critical role in the development of CS, acid scab and soil rot of sweet potato. In addition, the best-characterized CS-causing pathogen, Streptomyces scabies, produces a molecule that is predicted to resemble the Pseudomonas syringae coronatine phytotoxin and which contributes to seedling disease symptom development. Other Streptomyces phytotoxic secondary metabolites that have been identified include concanamycins, FD-891 and borrelidin. Furthermore, there is evidence that additional, unknown metabolites may participate in Streptomyces plant pathogenicity. Such revelations have implications for the rational development of better management procedures for controlling CS and other Streptomyces plant diseases.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Thaxtomins
  5. Biological activity of thaxtomins
  6. Biosynthesis of the thaxtomin phytotoxins
  7. Regulation of thaxtomin biosynthesis
  8. Concanamycins
  9. COR-like metabolites
  10. Bioactivity of the S. scabies COR-like metabolite
  11. Regulation of COR-like metabolite production in S. scabies
  12. FD-891
  13. Borrelidin
  14. Concluding remarks
  15. Acknowledgements
  16. Conflict of interest
  17. References
  18. Supporting Information

Organisms belonging to the genus Streptomyces are well known for their filamentous morphology, their large genomes and their complex developmental life cycle that involves the production of desiccation-resistant spores. The vast majority of Streptomyces spp. are soil-dwelling saprophytes that degrade recalcitrant biological polymers and contribute to the recycling of nutrients in the environment. Furthermore, these organisms are renowned for their ability to synthesize a wide array of medically and agriculturally useful secondary metabolites such as antibiotics, immunosuppressants, anti-tumour agents, insecticides and pesticides (Berdy 2005). Such compounds may provide a selective advantage to the producing organism by allowing it to compete with other micro-organisms for limited nutrients in the soil environment, and/or they may serve as facilitators of inter- and intra-generic communication (O'Brien and Wright 2011). In addition, some secondary metabolites are thought to promote symbiotic relationships between Streptomyces spp. and eukaryotic organisms (Seipke et al. 2012). An example of this is the involvement of secondary metabolites in parasitic relationships between plant pathogenic Streptomyces spp. and various plant hosts, a subject that is the focus of this review.

The ability to colonize living plant tissues and to cause plant diseases is a rare trait among the streptomycetes. Species that have this ability infect the underground portions of a wide variety of economically important crops, while above-ground parts of the plant will generally remain healthy unless nutrient and water transport between the roots and the shoots is hindered by the infection (Dees and Wanner 2012). The most important host that is affected by plant pathogenic streptomycetes is potato (Solanum tuberosum), and as such most of the research to date has focused on the diseases affecting this crop. However, those species causing scab disease of potato are neither tissue—nor host—specific and can infect potato as well as tap root crops such as carrot, beet, radish and parsnip under field conditions (Dees and Wanner 2012). Furthermore, such species can infect the seedlings of a variety of monocot and dicot plants under controlled conditions, leading to root and shoot stunting, cell hypertrophy and tissue necrosis (Leiner et al. 1996).

Potato common scab (CS) is considered the most important disease caused by Streptomyces spp. and is characterized by the formation of superficial, raised or pitted lesions on the surface of potato tubers (Loria et al. 1997). Such lesions reduce the market value of the potato crop and result in significant economic losses to growers. Several Streptomyces spp. are responsible for the disease (Table 1), of which S. scabies (syn. S. scabiei) was the first to be described and is the best-characterized and most widely distributed species. In addition to CS, S. scabies is responsible for pod wart of peanut, which is characterized by raised necrotic lesions on the peanut pericarp (Loria et al. 1997). Another disease, called acid scab (AS), is caused by Streptomyces acidiscabies and results in the same symptoms as CS except that the disease occurs in acid soils where CS is normally suppressed (Loria et al. 2006). Netted scab (NS) is a potato disease that has been reported mainly in Europe and is characterized by the formation of brown, superficial lesions with a netted appearance on the tuber surface. Unlike CS and AS, NS also causes severe necrosis of the fibrous roots of the potato plant and results in significant yield losses (Loria et al. 1997). Russet scab (RS) is similar to NS in that the lesions on the potato are superficial and are limited to the tuber periderm. However, the lesions do not have the netted pattern that is characteristic of NS, and root necrosis and yield losses have not been reported with this disease (Loria et al. 1997). Soil rot of sweet potato is caused by Streptomyces ipomoeae, which infects the fibrous roots of sweet potato (Ipomoea batatas (L.) Lam.), leading to tissue necrosis and death, and subsequent yield losses. Furthermore, the pathogen induces necrotic lesions on the fleshy storage roots, resulting in reduced marketability (Loria et al. 1997).

Table 1. Pathogenic Streptomyces spp. and associated plant disease(s) and phytotoxin(s) produced
SpeciesDisease(s) causedaPhytotoxin(s) producedReference(s)
  1. a

    CS, Common scab; AS, acid scab; NS, netted scab; RS, russet scab.

S. scabies (S. scabiei)CS, Pod wart of peanutThaxtomins, concanamycin A and B, COR-like metabolite(s)King et al. (1989, 1992); Natsume et al. (1996, 1998, 2001); Bignell et al. (2010b)
Streptomyces turgidiscabies CSThaxtominsBukhalid et al. (1998)
Streptomyces acidiscabies ASThaxtominsBukhalid et al. (1998)
Streptomyces europaeiscabiei CS, NSThaxtominsLoria et al. (2006)
Streptomyces reticuliscabiei NSUnknownBouchek-Mechiche et al. (2000)
Streptomyces stelliscabiei CSThaxtominsLoria et al. (2006)
Streptomyces luridiscabiei CSUnknownPark et al. (2003)
Streptomyces niveiscabiei CSUnknownPark et al. (2003)
Streptomyces puniciscabiei CSUnknownPark et al. (2003)
Streptomyces spp. IdahoXCSThaxtominsWanner (2007)
Streptomyces spp. DS3024CSThaxtominsHao et al. (2009)
Streptomyces spp. GK18CSBorrelidinCao et al. (2012)
Streptomyces cheloniumii RSFD-891Natsume et al. (2005)
Streptomyces spp. MAFF225003RSFD-891Natsume et al. (2005)
Streptomyces spp. MAFF225004RSFD-891Natsume et al. (2005)
Streptomyces spp. MAFF225005RSFD-891Natsume et al. (2005)
Streptomyces spp. MAFF225006RSFD-891Natsume et al. (2005)
Streptomyces ipomoeae Soil rot of sweet potatoThaxtominsKing et al. (1994); Guan et al. (2012)

This review focuses on the recent progress of research into the phytotoxic secondary metabolites that contribute to Streptomyces—plant interactions and to the development of plant diseases. Much of the discussion will focus on the thaxtomin phytotoxins, which play a critical role in the development of CS, AS and soil rot of sweet potato; however, recent research has suggested that additional phytotoxic secondary metabolites may also contribute to the development of these and other plant diseases in natural settings, and therefore such phytotoxins will also be addressed here.

Thaxtomins

  1. Top of page
  2. Summary
  3. Introduction
  4. Thaxtomins
  5. Biological activity of thaxtomins
  6. Biosynthesis of the thaxtomin phytotoxins
  7. Regulation of thaxtomin biosynthesis
  8. Concanamycins
  9. COR-like metabolites
  10. Bioactivity of the S. scabies COR-like metabolite
  11. Regulation of COR-like metabolite production in S. scabies
  12. FD-891
  13. Borrelidin
  14. Concluding remarks
  15. Acknowledgements
  16. Conflict of interest
  17. References
  18. Supporting Information

The first phytotoxic secondary metabolites associated with Streptomyces plant pathogenicity were reported in 1989 by King and colleagues (King et al. 1989), who described the isolation of two members of the thaxtomin family of phytotoxins associated with CS disease. Thaxtomins are cyclic dipeptides (2,5-diketopiperazines) derived from the condensation of l-phenylalanine and l-4-nitrotryptophan moieties (reviewed in King and Calhoun 2009). Eleven members of the thaxtomin family have been identified and characterized, with each member differing only in the presence or absence of hydroxyl and N-methyl groups at specific sites (King and Calhoun 2009). The 4-nitro moiety, together with the l,l configuration of the tryptophan and phenylalanine groups, have been shown to be essential for the phytotoxic activity of these compounds (King et al. 1989, 1992). Thaxtomin A (Fig. 1a) is the primary family member produced by S. scabies, S. acidiscabies and Streptomyces turgidiscabies, although other family members have been shown to be produced in minor amounts (King and Calhoun 2009). Thaxtomin C (Fig. 1a), which is a less modified, nonhydroxylated family member, is the major product synthesized by S. ipomoeae (King et al. 1994; Guan et al. 2012).

image

Figure 1. Molecular structure of the thaxtomin A and C (a), concanamycin A and B (b), FD-891 (c) and borrelidin (d) phytotoxins that are produced by plant pathogenic Streptomyces spp.

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Biological activity of thaxtomins

  1. Top of page
  2. Summary
  3. Introduction
  4. Thaxtomins
  5. Biological activity of thaxtomins
  6. Biosynthesis of the thaxtomin phytotoxins
  7. Regulation of thaxtomin biosynthesis
  8. Concanamycins
  9. COR-like metabolites
  10. Bioactivity of the S. scabies COR-like metabolite
  11. Regulation of COR-like metabolite production in S. scabies
  12. FD-891
  13. Borrelidin
  14. Concluding remarks
  15. Acknowledgements
  16. Conflict of interest
  17. References
  18. Supporting Information

Thaxtomins have the ability to cause necrosis on excised potato tuber tissue (Loria et al. 2006), and they can induce scab-like lesions on aseptically cultured minitubers (Lawrence et al. 1990). In addition, nanomolar concentrations of thaxtomin A cause root and shoot stunting and radial swelling of monocot and dicot seedlings, effects that mimic the seedling disease symptoms caused by S. scabies and S. acidiscabies (Leiner et al. 1996; Loria et al. 1997). A positive correlation has been observed between the ability to produce thaxtomin A and the pathogenicity of scab-causing Streptomyces spp. (King et al. 1991; Loria et al. 1995; Goyer et al. 1998; Kinkel et al. 1998), and a constructed thaxtomin mutant of S. acidiscabies could not induce typical scab lesions on potato minitubers (Healy et al. 2000). Recently, it was shown that S. ipomoeae thaxtomin C mutants are unable to penetrate the intact adventitious roots of sweet potato plants (Guan et al. 2012). Thus, the thaxtomin phytotoxins are an essential virulence factor in several plant pathogenic Streptomyces spp.

A number of physiological effects in plants have been reported to occur in response to thaxtomins, including alterations in plant Ca2+ and H+ ion influx, induction of programmed cell death, and production of the antimicrobial plant phytoalexin scopoletin (Duval et al. 2005; Tegg et al. 2005; Errakhi et al. 2008; Lerat et al. 2009). Fry and Loria noted that nanomolar concentrations of thaxtomin A cause plant cell hypertrophy in onion seedling hypocotyls, radish seedling hypocotyls and tobacco suspension cultures (Fry and Loria 2002). It also interferes with cytokinesis in onion root tip cells, and it inhibits normal cell elongation of tobacco protoplasts (Fry and Loria 2002). This, in turn, led the authors to propose that thaxtomin A targets the plant cell wall. Further evidence for a cell wall target was provided by Scheible et al., who demonstrated that thaxtomin A inhibits the incorporation of 14C-glucose into the cellulosic fraction of the cell wall in Arabidopsis thaliana (Scheible et al. 2003). More recently, Bischoff et al. showed that thaxtomin A reduces the crystalline cellulose content of A. thaliana plant cell walls, and it affects the expression of cell wall synthesis genes in a similar manner as the known cellulose synthesis inhibitor isoxaben. Furthermore, spinning disc confocal microscopy revealed that thaxtomin A depletes cellulose synthase complexes from A. thaliana plasma membranes (Bischoff et al. 2009). Duval and Beaudoin used whole genome microarrays to show that thaxtomin A and isoxaben elicit a similar gene expression profile in A. thaliana cell suspensions (Duval and Beaudoin 2009). Taken together, the results suggest that the primary mode of action of thaxtomin A is the inhibition of cellulose biosynthesis.

Biosynthesis of the thaxtomin phytotoxins

  1. Top of page
  2. Summary
  3. Introduction
  4. Thaxtomins
  5. Biological activity of thaxtomins
  6. Biosynthesis of the thaxtomin phytotoxins
  7. Regulation of thaxtomin biosynthesis
  8. Concanamycins
  9. COR-like metabolites
  10. Bioactivity of the S. scabies COR-like metabolite
  11. Regulation of COR-like metabolite production in S. scabies
  12. FD-891
  13. Borrelidin
  14. Concluding remarks
  15. Acknowledgements
  16. Conflict of interest
  17. References
  18. Supporting Information

As with other Streptomyces secondary metabolites, the biosynthetic genes for the thaxtomin phytotoxins (txt) are clustered together on the chromosome of S. scabies, S. turgidiscabies, S. acidiscabies and S. ipomoeae (Loria et al. 2008; Guan et al. 2012). The genes are arranged in at least two operons, with the first likely consisting of txtA, txtB, txtH and possibly txtC, and the second consisting of nos/txtD and txtE, the co-transcription of which has been confirmed (Barry et al. 2012). Analysis of the encoded protein products indicates a high degree of conservation among the four distantly related species, although it is apparent that the conservation is considerably higher among the scab-causing pathogens (Table 2). This, together with the localization of the txt gene cluster on a mobile pathogenicity island in S. turgidiscabies (Kers et al. 2005; Huguet-Tapia et al. 2011), suggests that horizontal gene transfer likely played a role in the acquisition of the txt gene cluster by Streptomyces spp.

Table 2. Proteins encoded by the S. scabies thaxtomin biosynthetic gene cluster and their % identity/similarity to homologues in other plant pathogenic Streptomyces spp.
Txt Proteins from Streptomyces scabies 87-22Function% Identity/similarity to Streptomyces turgidiscabies Car8 Txt homologues% Identity/similarity to Streptomyces acidiscabies 84.104 Txt homologues% Identity/similarity to Streptomyces ipomoeae 91-03 Txt homologues
TxtASynthesis of thaxtomin backbone90/93100/10050/60
TxtBSynthesis of thaxtomin backbone90/9399/9960/70
TxtCHydroxylation of thaxtomin backbone90/93100/100Absent
TxtDNitration of l-tryptophan precursor91/93100/10075/83
TxtENitration of l-tryptophan precursor88/94100/10085/91
TxtHUnknown81/85100/10063/69
TxtRRegulation of thaxtomin biosynthesis78/83100/10042/58

The biosynthesis of the thaxtomin phytotoxins begins with the production of nitric oxide (NO) from arginine, a reaction that is catalysed by the TxtD nitric oxide synthase (Kers et al. 2004). NO is then used for the site-specific nitration of l-tryptophan by TxtE, which is a novel cytochrome P450 (Barry et al. 2012). Deletion analysis of the txtE gene in S. turgidiscabies confirmed that it is essential for thaxtomin A biosynthesis, while addition of l-4-nitrotryptophan to cultures of the ΔtxtE strain restored thaxtomin A production (Barry et al. 2012). This, together with the fact that l-4-nitrotryptophan accumulates in cultures of the S. scabies txtA and txtB mutants (Johnson et al. 2009), indicates that the production of l-4-nitrotryptophan is the first committed step in the thaxtomin biosynthetic pathway. l-4-nitrotryptophan then serves as a substrate for the TxtB nonribosomal peptide synthetase (NRPS), while l-phenylalanine is the substrate for the TxtA NRPS (Johnson et al. 2009). In the case of thaxtomin A biosynthesis, the resulting cyclo-(l-4-nitrotryptophyl-l-phenylalanyl) intermediate (called thaxtomin D) is N-methylated on both the nitrotryptophyl and phenylalanyl moieties (Healy et al. 2002), and it is presumed that the methylation is catalysed by the S-adenosylmethionine-dependent N-methyltransferase domain found in both TxtA and TxtB. It has previously been reported that N-methyl-l-4-nitrotryptophan can accumulate in the culture supernatants of wild-type S. scabies (King and Lawrence 1995) and of a S. scabies ΔtxtA mutant (Johnson et al. 2009), which suggests that the N-methylation occurs prior to cyclic dipeptide formation. Interestingly, the S. ipomoeae TxtAB homologues are also predicted to each contain an N-methyltransferase domain, and yet thaxtomin C is only N-methylated on the nitrotryptophanyl moiety (Fig. 1a). The final step in thaxtomin A biosynthesis is the addition of hydroxyl groups to the phenylalanyl moiety of thaxtomin D by the TxtC P450 monooxygenase. Deletion analysis of txtC in S. acidiscabies led to the accumulation of thaxtomin D in the culture supernatant, confirming the role of TxtC in postcyclization hydroxylation (Healy et al. 2002). Notably, txtC is absent from the S. ipomoeae txt gene cluster, and no homologue appears to exist anywhere else in the S. ipomoeae genome (Bignell et al. 2010a; Guan et al. 2012), an observation that is consistent with the fact that this organism does not produce thaxtomin A (King et al. 1994).

An additional gene (txtH) that was recently identified in the thaxtomin biosynthetic gene cluster of S. scabies (Bignell et al. 2010a) is predicted to encode a member of the MbtH-like protein superfamily. MbtH-like proteins are small proteins (normally 62–80 amino acids) that are often associated with NRPS gene clusters (reviewed in Baltz 2011). Deletion studies have shown that some MbtH-like proteins are necessary for production of the corresponding metabolite, whereas in other instances, deletion of the MbtH-like protein-encoding gene does not have any effect. The latter is often due to the presence of other MbtH-like protein-encoding genes elsewhere in the genome that can cross complement the deleted gene with varying efficiencies. Recent biochemical studies have shown that some MbtH-like proteins can be co-purified with their cognate NRPS and that they function to facilitate the adenylation reaction catalysed by the NRPS adenylation domain (Baltz 2011 and references therein). The S. scabies txtH gene is conserved in the txt gene clusters of S. turgidiscabies, S. acidiscabies and S. ipomoeae, suggesting that it may be important for the biosynthesis of thaxtomins (Table 2). However, it is noteworthy that the genome sequences for all four pathogens contain multiple predicted MbtH-like protein-encoding genes, and therefore the possibility exists for cross-complementation to occur in each organism.

Regulation of thaxtomin biosynthesis

  1. Top of page
  2. Summary
  3. Introduction
  4. Thaxtomins
  5. Biological activity of thaxtomins
  6. Biosynthesis of the thaxtomin phytotoxins
  7. Regulation of thaxtomin biosynthesis
  8. Concanamycins
  9. COR-like metabolites
  10. Bioactivity of the S. scabies COR-like metabolite
  11. Regulation of COR-like metabolite production in S. scabies
  12. FD-891
  13. Borrelidin
  14. Concluding remarks
  15. Acknowledgements
  16. Conflict of interest
  17. References
  18. Supporting Information

The production of thaxtomin A by scab-causing streptomycetes is affected by several physiological and environmental signals. For example, production does not take place in common microbiological growth media such as LB and tryptic soy broth (Loria et al. 1995), whereas it readily occurs in living host tissue or in plant-based media such as potato broth, oatmeal broth or oat bran broth (Babcock et al. 1993; Loria et al. 1995; King and Lawrence 1996; Goyer et al. 1998). Glucose appears to repress the biosynthesis of thaxtomin in liquid growth media (Babcock et al. 1993; Loria et al. 1995), a phenomenon that has been reported for other Streptomyces secondary metabolites (Ruiz et al. 2010). Aromatic amino acids such as tryptophan, tyrosine and phenylalanine have also been shown to inhibit phytotoxin biosynthesis, whereas aliphatic amino acids have no effect (Babcock et al. 1993; Lauzier et al. 2002).

Recent work has identified specific plant-based compounds that are capable of stimulating thaxtomin A biosynthesis. Wach et al. (2007) demonstrated that the addition of xylans, glucans and cellobiose to oat bran broth medium stimulates higher levels of thaxtomin A production in S. acidiscabies compared to the unamended control, while Johnson et al. (2007) showed that the cellobiose and cellotriose could stimulate txt gene expression and phytotoxin production in a defined minimal medium. Moreover, suberin, which is a complex plant polymer found on the surface of potato tubers, has been shown to stimulate phytotoxin production in a minimal medium (Beausejour et al. 1999), and more recently it was demonstrated that the addition of both suberin and cellobiose to a minimal medium stimulates much higher txt gene expression and thaxtomin A production then when cellobiose or suberin are added separately (Lerat et al. 2010).

Embedded within the txt gene clusters of S. scabies, S. turgidiscabies and S. acidiscabies is a gene (txtR) that encodes an AraC-family transcriptional regulator (Table 2; Joshi et al. 2007). Given that regulatory genes are often associated with secondary metabolite biosynthetic gene clusters and that they function to control the production of the corresponding metabolite (van Wezel and McDowall 2011), it was hypothesized that TxtR likely serves as a regulator of thaxtomin biosynthesis in these organisms. This was confirmed by constructing a S. scabies ΔtxtR mutant and showing that it produced only trace levels of thaxtomin A, was reduced in expression of the thaxtomin biosynthetic genes, and was avirulent on tobacco and radish seedlings (Joshi et al. 2007; Loria et al. 2008). Interestingly, the expression of the txtR gene in S. scabies and S. turgidiscabies was shown to be dependent on cellobiose (Johnson et al. 2007; Joshi et al. 2007), and cellobiose was demonstrated to serve as a ligand for the S. scabies TxtR protein in a pull-down assay (Joshi et al. 2007). Given that thaxtomin A targets cellulose biosynthesis and that cellobiose is the smallest subunit of cellulose, it has been proposed that cellobiose and possibly other cello-oligosaccharides may serve as a signal for the presence of active plant cell growth and tissue expansion where cellulose synthesis takes place, and that stimulation of thaxtomin A production by cellobiose may allow penetration of the expanding tissue by the pathogen (Loria et al. 2008). Whether suberin or breakdown products of suberin also serve as signals that are sensed by TxtR remains to be determined; however, as it was recently shown that suberin induces the onset of morphological differentiation and secondary metabolism in both pathogenic and nonpathogenic streptomycetes (Lerat et al. 2012), it is likely that the effect of suberin is not specific to the thaxtomin phytotoxins.

Recently, a txtR homologue was reported in the txt gene cluster of S. ipomoeae (Guan et al. 2012). The resulting protein product shows only weak similarity to the TxtR protein from S. scabies (Table 2), which might reflect differences in the regulation of thaxtomin production in the scab-causing pathogens and in S. ipomoeae. Specifically, thaxtomin C in S. ipomoeae is not produced in the same plant-based media that induce thaxtomin A production (King et al. 1994; Guan et al. 2012), which suggests that cello-oligosaccharides do not function as inducers of thaxtomin C production. The exact ligand(s) that interacts with the S. ipomoeae TxtR remains to be determined, but it is intriguing to speculate that the ligand(s) is a plant-derived molecule that is specific to the Convolvulaceae family, and that this might account for the observed narrow host range of S. ipomoeae as compared to the scab-causing pathogens (Guan et al. 2012).

Concanamycins

  1. Top of page
  2. Summary
  3. Introduction
  4. Thaxtomins
  5. Biological activity of thaxtomins
  6. Biosynthesis of the thaxtomin phytotoxins
  7. Regulation of thaxtomin biosynthesis
  8. Concanamycins
  9. COR-like metabolites
  10. Bioactivity of the S. scabies COR-like metabolite
  11. Regulation of COR-like metabolite production in S. scabies
  12. FD-891
  13. Borrelidin
  14. Concluding remarks
  15. Acknowledgements
  16. Conflict of interest
  17. References
  18. Supporting Information

In addition to thaxtomins, S. scabies has been reported to produce two members of the concanamycin family of secondary metabolites (Table 1). Concanamycins are polyketide macrolides that were first isolated from the culture medium of S. diastatochromogenes (Kinashi et al. 1984). They are characterized by an 18-membered tetraenic macrolide ring with a methyl enol ether and a β-hydroxyhemiacetyl side chain (Fig. 1b), and they function as vacuolar-type ATPase inhibitors and exhibit antifungal and anti-neoplastic activity but not antibacterial activity (Kinashi et al. 1984; Seki-Asano et al. 1994). Natsume and colleagues were the first to report the isolation of S. scabies strains from Japan that produced concanamycin A and B, and rice seedling bioassays demonstrated that the pure compounds exhibit root growth inhibitory activity (Natsume et al. 1996, 1998). The genome sequence of S. scabies 87–22 contains a biosynthetic gene cluster that is highly similar to the concanamycin biosynthetic gene cluster from Streptomyces neyagawaensis (Haydock et al. 2005), suggesting that this strain of S. scabies also produces concanamycins. The contribution of concanamycins to CS disease needs further clarification given that other characterized CS pathogens do not appear to produce these compounds (Natsume et al. 1998, 2001, 2005).

COR-like metabolites

  1. Top of page
  2. Summary
  3. Introduction
  4. Thaxtomins
  5. Biological activity of thaxtomins
  6. Biosynthesis of the thaxtomin phytotoxins
  7. Regulation of thaxtomin biosynthesis
  8. Concanamycins
  9. COR-like metabolites
  10. Bioactivity of the S. scabies COR-like metabolite
  11. Regulation of COR-like metabolite production in S. scabies
  12. FD-891
  13. Borrelidin
  14. Concluding remarks
  15. Acknowledgements
  16. Conflict of interest
  17. References
  18. Supporting Information

Genome sequencing of S. scabies strain 87–22 revealed the presence of a biosynthetic gene cluster that is highly similar to the coronafacic acid (CFA) biosynthetic gene cluster from the Gram-negative plant pathogens Pseudomonas syringae and Pectobacterium atrosepticum (Bignell et al. 2010b). CFA (Fig. 2a) is the polyketide component of coronatine (COR) (Fig. 2b), which is a nonhost specific phytotoxin produced by different pathovars of Ps. syringae (Gross and Loper 2009). The COR molecule consists of CFA linked via an amide bond to an ethylcyclopropyl amino acid called coronamic acid (CMA), which is derived from l-allo-isoleucine (Gross and Loper 2009). Although COR is the primary metabolite produced by Ps. syringae and is the most toxic, other coronafacoyl compounds in which CFA is linked to various amino acids have been reported, including CFA-isoleucine, CFA-allo-isoleucine, CFA-valine and CFA-norvaline (Fig. 2c–f; Bender et al. 1999).

image

Figure 2. Molecular structure of coronafacic acid (CFA) (a), coronatine (COR) (b), CFA-isoleucine (c), CFA-allo-isoleucine (d), CFA-valine (e) and CFA-norvaline (f) produced by Pseudomonas syringae.

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The CFA-like biosynthetic gene cluster identified in S. scabies 87–22 consists of at least 15 genes, nine of which are homologous to genes from the CFA biosynthetic gene clusters of Ps. syringae pv. tomato and P. atrosepticum (Bignell et al. 2010b). These include the cfa1-5 genes that encode enzymes believed to synthesize the 2-carboxy-2-cyclopentenone intermediate (CPC), as well as the cfa6 and cfa7 genes, which encode the large multidomain polyketide synthases (PKSs) that generate the CFA backbone from CPC (Rangaswamy et al. 1998). In addition, the cfl gene, which in Ps. syringae encodes an enzyme that is believed to catalyse the adenylation of CFA and the ligation of the CFA adenylate to CMA (Bender et al. 1999), is also conserved in S. scabies. Although S. scabies is unable to produce COR due to the absence of the CMA biosynthetic genes in the genome (Bignell et al. 2010b), it is likely that this organism produces one or more COR-like metabolites that are similar to the minor coronafacoyl compounds that are generated by Ps. syringae (Fig. 2c–f).

It is interesting to note that there are six genes within the S. scabies CFA-like biosynthetic gene cluster that are absent from the Ps. syringae and P. atrosepticum CFA biosynthetic gene clusters, and at least three of these genes are predicted to encode enzymes that could potentially modify the CFA polyketide backbone (Bignell et al. 2010b). Furthermore, the S. scabies Cfa7 enzyme contains an enoyl reductase domain that is absent from the Cfa7 homologues in Ps. syringae and P. atrosepticum (Bignell et al. 2010b), and if active, this domain would presumably reduce the carbon double bond that is present in CFA (Fig. 2b). Purification and structural analysis of the COR-like metabolite is currently ongoing within our laboratory, and this will provide insight into whether the molecule is novel in structure as compared to COR and the COR analogues produced by Ps. syringae.

Bioactivity of the S. scabies COR-like metabolite

  1. Top of page
  2. Summary
  3. Introduction
  4. Thaxtomins
  5. Biological activity of thaxtomins
  6. Biosynthesis of the thaxtomin phytotoxins
  7. Regulation of thaxtomin biosynthesis
  8. Concanamycins
  9. COR-like metabolites
  10. Bioactivity of the S. scabies COR-like metabolite
  11. Regulation of COR-like metabolite production in S. scabies
  12. FD-891
  13. Borrelidin
  14. Concluding remarks
  15. Acknowledgements
  16. Conflict of interest
  17. References
  18. Supporting Information

Gene deletion studies in S. scabies have demonstrated that the COR-like metabolite contributes to the development of root disease symptoms in tobacco seedlings (Bignell et al. 2010a,b), and this correlates with the observed role of COR as an important contributor of disease symptom development during Ps. syringae infections (Xin and He 2013). Whether the COR-like metabolite also influences the severity of CS disease symptoms has not been determined, but is something that does warrant further investigation. However, it is likely that the metabolite is not required for CS disease development as other CS pathogens do not appear to produce it (Bignell et al. 2010b). It is noteworthy that the metabolite can cause hypertrophy of potato tuber tissue in a similar manner as COR (Fig. 3), suggesting that it may share the same target(s) in the plant host. It has been determined that COR functions as a molecular mimic of jasmonoyl—isoleucine (JA-Ile), which is the active form of the jasmonic acid (JA) plant hormone (Katsir et al. 2008a,b). JA-Ile controls the expression of genes involved in plant growth, development and defence against herbivores and necrotrophic pathogens (Browse and Howe 2008). When JA-responsive genes are activated, this leads to suppression of salicylic acid (SA)—mediated defence pathways, which are important for defence against biotrophic pathogens such as Ps. syringae (Koornneef and Pieterse 2008). Thus by functioning as a molecular mimic of JA-Ile, COR suppresses the plant defence response that is most important for combating infection by Ps. syringae. It is possible that the S. scabies COR-like metabolite also functions in a similar manner to allow the pathogen to overcome the host immune response, an idea that is currently under investigation in our laboratory.

image

Figure 3. Induction of potato tissue hypertrophy by the S. scabies coronatine (COR)-like metabolite. Potato tuber disks were treated with COR (250 ng) (a) or with culture extract from a S. scabies COR-like metabolite-producing strain (c). Control treatments included 100% methanol (b) and culture extract from a S. scabies COR-like metabolite nonproducing strain (d).

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Regulation of COR-like metabolite production in S. scabies

  1. Top of page
  2. Summary
  3. Introduction
  4. Thaxtomins
  5. Biological activity of thaxtomins
  6. Biosynthesis of the thaxtomin phytotoxins
  7. Regulation of thaxtomin biosynthesis
  8. Concanamycins
  9. COR-like metabolites
  10. Bioactivity of the S. scabies COR-like metabolite
  11. Regulation of COR-like metabolite production in S. scabies
  12. FD-891
  13. Borrelidin
  14. Concluding remarks
  15. Acknowledgements
  16. Conflict of interest
  17. References
  18. Supporting Information

Embedded within the CFA-like biosynthetic gene cluster in S. scabies is a gene (scab79591; referred to herein as cfaR) that was previously shown to modulate the expression of the biosynthetic genes within the cluster (Bignell et al. 2010b). The encoded protein belongs to a novel family of transcriptional regulators that are only found in actinobacteria and are characterized by a C-terminal LuxR- family DNA-binding domain and an N-terminal PAS fold domain. The best-characterized member of this family is PimM, which controls the production of the polyene macrolide pimaricin in Streptomyces natalensis. PimM is required for expression of the pimaricin biosynthetic genes and for pimaricin production (Anton et al. 2007), and it has been shown to directly bind eight promoter regions within the biosynthetic gene cluster (Santos-Aberturas et al. 2011b). In addition, a ΔpimM mutant can be complemented by other closely related members of the PAS-LuxR family such as amphRIV, nysRIV and pteF, which are associated with the amphotericin, nystatin and filipin polyene macrolide biosynthetic clusters, respectively, and heterologous expression of pimM can enhance the biosynthesis of amphotericin and filipin in the respective producing organisms (Santos-Aberturas et al. 2011a). Together, this suggests that there is functional conservation among these members of the PAS-LuxR protein family. Genetic studies have shown that CfaR functions as a positive activator of gene expression in the CFA-like gene cluster (Bignell et al. 2010b), and electrophoretic mobility shift assays have confirmed that the protein directly binds to DNA within the cluster (Z. Cheng, unpublished data). It is currently not clear how the DNA binding activity of CfaR is regulated, although this is presumed to somehow involve the associated PAS domain. Interestingly, phylogenetic analysis suggests that CfaR may represent a novel member of the PAS-LuxR family as the protein does not appear to cluster with other family members in the database (Fig. 4).

image

Figure 4. Phylogenetic analysis of PAS-LuxR family proteins from Streptomyces and other actinomycetes. The tree was constructed using the MEGA 5.2 software (Tamura et al. 2011) with the maximum likelihood algorithm. Bootstrap values ≥50% for 1000 repetitions are indicated. The scale bar indicates the number of amino acid substitutions per site. Accession numbers for the protein sequences used in this analysis are listed in Table S1. The Aliivibrio fischeri LuxR protein was included as an outgroup.

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FD-891

  1. Top of page
  2. Summary
  3. Introduction
  4. Thaxtomins
  5. Biological activity of thaxtomins
  6. Biosynthesis of the thaxtomin phytotoxins
  7. Regulation of thaxtomin biosynthesis
  8. Concanamycins
  9. COR-like metabolites
  10. Bioactivity of the S. scabies COR-like metabolite
  11. Regulation of COR-like metabolite production in S. scabies
  12. FD-891
  13. Borrelidin
  14. Concluding remarks
  15. Acknowledgements
  16. Conflict of interest
  17. References
  18. Supporting Information

Streptomyces cheloniumii (Table 1) is a new species of Streptomyces that was isolated in Japan and causes RS but not CS on potato tubers (Oniki et al. 1986). In 2005, Natsume and colleagues reported the isolation of a new phytotoxin produced by S. cheloniumii and four other Streptomyces strains isolated from Japan (Natsume et al. 2005). Bioassays indicated that the phytotoxic compound induces necrosis of potato tuber tissue and causes stunting of rice and alfalfa seedlings, indicating that like thaxtomin A, it is a nonspecific phytotoxin. Purification and structural analysis of the phytotoxic compound identified it as the 16-membered macrolide FD-891 (Fig. 1c; Seki-Asano et al. 1994; Eguchi et al. 2004). FD-891 was previously reported to have cytocidal activity against animal cells (Seki-Asano et al. 1994), and the report by Natsume et al. is the first to describe its phytotoxicity (Natsume et al. 2005). Although FD-891 has a similar structure to the concanamycins (Fig. 1), the mode of action of the two types of metabolites appears to be different (Kataoka et al. 2000). It is currently not clear whether other RS-causing pathogens from other parts of the world also produce FD-891, and the contribution of FD-891 to RS disease symptom development also remains to be determined.

Borrelidin

  1. Top of page
  2. Summary
  3. Introduction
  4. Thaxtomins
  5. Biological activity of thaxtomins
  6. Biosynthesis of the thaxtomin phytotoxins
  7. Regulation of thaxtomin biosynthesis
  8. Concanamycins
  9. COR-like metabolites
  10. Bioactivity of the S. scabies COR-like metabolite
  11. Regulation of COR-like metabolite production in S. scabies
  12. FD-891
  13. Borrelidin
  14. Concluding remarks
  15. Acknowledgements
  16. Conflict of interest
  17. References
  18. Supporting Information

Recently, a new pathogenic strain of Streptomyces was isolated from a scab lesion on a potato grown in Iran (Cao et al. 2012). The strain (GK18) was shown to induce deep pitted lesions on potato tubers rather than the raised lesions that are typically caused by S. scabies and other thaxtomin-producing species, and it also caused severe stunting of potato plants grown in pots. Interestingly, the authors could not detect thaxtomin A production by this strain, nor could they detect the txtA gene using Southern analysis. Instead, the strain was shown to produce the 18-membered polyketide macrolide borrelidin (Fig. 1d), which was first identified as an antibacterial antibiotic produced by Streptomyces rochei (Berger et al. 1949). Southern analysis confirmed that strain GK18 contains genes involved in the biosynthesis of borrelidin, and bioassays using potato tuber slices and radish seedlings demonstrated that the borrelidin purified from GK18 culture extracts exhibits phytotoxic activity. Interestingly, borrelidin was reported to cause deep, black holes on the potato tuber slices, an effect that is reminiscent of the disease symptoms caused by Streptomyces spp. GK18 on mini tubers. Thaxtomin A, on the other hand, produced more shallow, brown lesions on the potato tuber slices. Thus, it appears as though different Streptomyces phytotoxins can contribute to the production of distinct types of scab symptoms on potato tubers, and that production of different phytotoxins by different pathogenic streptomycetes might explain in some instances why there are several types of disease symptoms associated with CS disease in natural settings.

Borrelidin has been shown to exhibit anti-bacterial, anti-viral, anti-malarial and anti-angiogenic activity (Dickinson et al. 1965; Wakabayashi et al. 1997; Otoguro et al. 2003); however, the report by Cao and colleagues is the first to demonstrate that this metabolite also exhibits phytotoxic activity (Cao et al. 2012). Furthermore, the report supports previous findings (Park et al. 2003; Wanner 2004) that some CS-causing streptomycetes do not produce thaxtomin A. It is noteworthy that Cao and colleagues were able to isolate 17 additional CS-causing streptomycetes, none of which produced thaxtomin A or borrelidin (Cao et al. 2012). Furthermore, research in our own laboratory has led to the isolation of two Streptomyces strains from Newfoundland, Canada that are pathogenic on radish seedlings (Fig. 5) and on potato tuber disks (data not shown), and yet they do not appear to produce thaxtomins, borrelidin or concanamycins (J. Fyans, unpublished). It therefore appears as though additional, unknown phytotoxic secondary metabolites are possibly contributing to Streptomyces plant pathogenicity in the environment, and the identification and characterization of such metabolites will undoubtedly contribute to a better understanding of the mechanisms of disease development by these organisms.

image

Figure 5. Virulence phenotype of nonthaxtomin-producing plant pathogenic Streptomyces strains isolated from Newfoundland, Canada. Radish seedlings were inoculated with Streptomyces spp. 11-1-2 (c) and 11-2-4 (d), whereas control seedlings were treated with water (a) or with S. scabies 87-22 (b).

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Concluding remarks

  1. Top of page
  2. Summary
  3. Introduction
  4. Thaxtomins
  5. Biological activity of thaxtomins
  6. Biosynthesis of the thaxtomin phytotoxins
  7. Regulation of thaxtomin biosynthesis
  8. Concanamycins
  9. COR-like metabolites
  10. Bioactivity of the S. scabies COR-like metabolite
  11. Regulation of COR-like metabolite production in S. scabies
  12. FD-891
  13. Borrelidin
  14. Concluding remarks
  15. Acknowledgements
  16. Conflict of interest
  17. References
  18. Supporting Information

Research over the last several years has provided important insights into plant pathogenic Streptomyces spp. and the phytotoxins that they produce to colonize and infect living plant tissues. Such information has assisted in the development of better procedures for detecting the pathogens in agricultural settings, and has provided new ideas for developing better control methods for reducing the economic impact of CS and other diseases. For example, the thaxtomin phytotoxins are now known to function as key virulence factors that are produced by several different CS and AS pathogens, and recent work using thaxtomin A as a selective agent has provided promising results for the development of potato lines that display elevated resistance to CS (Wilson et al. 2010; Hiltunen et al. 2011). This is significant given that CS is ubiquitous and notoriously difficult to effectively manage, and there are currently no potato cultivars that are completely resistant to the responsible pathogens (Dees and Wanner 2012). But, as discussed in this review, it is now apparent that multiple phytotoxic secondary metabolites are likely playing a role in the pathogenic phenotype of Streptomyces spp. in the environment, and thaxtomins are not always involved in the development of CS disease. This has important implications for control strategies that specifically target thaxtomin as such strategies will likely not be universally effective against all CS pathogens. Therefore, it is vital that we continue to decipher the role of secondary metabolism in the development of economically important crop diseases by Streptomyces spp. as this information is critical for the rational development of control strategies that will be effective in the long term. In addition, the functional analysis of Streptomyces secondary metabolites will help to further elucidate the complex mechanisms involved in host–pathogen interactions, which are ever evolving and dynamic processes.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Thaxtomins
  5. Biological activity of thaxtomins
  6. Biosynthesis of the thaxtomin phytotoxins
  7. Regulation of thaxtomin biosynthesis
  8. Concanamycins
  9. COR-like metabolites
  10. Bioactivity of the S. scabies COR-like metabolite
  11. Regulation of COR-like metabolite production in S. scabies
  12. FD-891
  13. Borrelidin
  14. Concluding remarks
  15. Acknowledgements
  16. Conflict of interest
  17. References
  18. Supporting Information

This study was supported by the Natural Sciences and Engineering Research Council of Canada, the Newfoundland and Labrador Research and Development Corporation, the Canadian Foundation for Innovation, and the Canada—Newfoundland Agriculture Research Initiative. We thank Dr. Kapil Tahlan as well as the anonymous reviewers for helpful comments on the manuscript.

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  1. Top of page
  2. Summary
  3. Introduction
  4. Thaxtomins
  5. Biological activity of thaxtomins
  6. Biosynthesis of the thaxtomin phytotoxins
  7. Regulation of thaxtomin biosynthesis
  8. Concanamycins
  9. COR-like metabolites
  10. Bioactivity of the S. scabies COR-like metabolite
  11. Regulation of COR-like metabolite production in S. scabies
  12. FD-891
  13. Borrelidin
  14. Concluding remarks
  15. Acknowledgements
  16. Conflict of interest
  17. References
  18. Supporting Information
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Supporting Information

  1. Top of page
  2. Summary
  3. Introduction
  4. Thaxtomins
  5. Biological activity of thaxtomins
  6. Biosynthesis of the thaxtomin phytotoxins
  7. Regulation of thaxtomin biosynthesis
  8. Concanamycins
  9. COR-like metabolites
  10. Bioactivity of the S. scabies COR-like metabolite
  11. Regulation of COR-like metabolite production in S. scabies
  12. FD-891
  13. Borrelidin
  14. Concluding remarks
  15. Acknowledgements
  16. Conflict of interest
  17. References
  18. Supporting Information
FilenameFormatSizeDescription
jam12369-sup-0001-TableS1.xlsxapplication/msexcel12K

Table S1 Accession numbers of the PAS-LuxR protein sequences used for construction of the phylogenetic tree.

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