Differential regulation of toxoflavin production and its role in the enhanced virulence of <i>Burkholderia gladioli</i>

Lee, Jongyun; Park, Jung–Wook; Kim, Sun‐Young; Park, Inmyoung; Seo, Young-Su

doi:10.1111/mpp.12262

Cited by 51 publications

(72 citation statements)

References 44 publications

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“…In fact, toxoflavin was known to be produced by B. gladioli (32), B. glumae (50,51), Pseudomonas protegens (52), and Streptomyces spp. (53).…”

Section: Discussionmentioning

confidence: 99%

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Toxoflavin Produced by Burkholderia gladioli from Lycoris aurea Is a New Broad-Spectrum Fungicide

Ren

et al. 2019

Appl Environ Microbiol

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Fungal infections not only cause extensive agricultural damage but also result in serious diseases in the immunodeficient populations of human beings. Moreover, the increasing emergence of drug resistance has led to a decrease in the efficacy of current antifungals. Thus, screening of new antifungal agents is imperative in the fight against antifungal drug resistance. In this study, we show that an endophytic bacterium, Burkholderia gladioli HDXY-02, isolated from the medicinal plant Lycoris aurea, showed broad-spectrum antifungal activity against plant and human fungal pathogens. An antifungal ability assay indicated that the bioactive component was produced from strain HDXY-02 having an extracellular secreted component with a molecular weight lower than 1,000 Da. In addition, we found that this new antifungal could be produced effectively by liquid fermentation of HDXY-02. Furthermore, the purified component contributing to the antifungal activity was identified to be toxoflavin, a yellow compound possessing a pyrimido [5,4-e] [1,2,4]triazine ring. In vitro bioactivity studies demonstrated that purified toxoflavin from B. gladioli HDXY-02 cultures had a significant antifungal activity against the human fungal pathogen Aspergillus fumigatus, resulting in abolished germination of conidia. More importantly, the growth inhibition by toxoflavin was observed in both wild-type and drug-resistant mutants (cyp51A and non-cyp51A) of A. fumigatus. Finally, an optimized protocol for the large-scale production of toxoflavin (1,533 mg/ liter) has been developed. Taken together, our findings provide a promising biosynthetic resource for producing a new antifungal reagent, toxoflavin, from isolates of the endophytic bacterium B. gladioli. IMPORTANCE Human fungal infections are a growing problem associated with increased morbidity and mortality. Moreover, a growing number of antifungal-resistant fungal isolates have been reported over the past decade. Thus, the need for novel antifungal agents is imperative. In this study, we show that an endophytic bacterium, Burkholderia gladioli, isolated from the medicinal plant Lycoris aurea, is able to abundantly secrete a compound, toxoflavin, which has a strong fungicidal activity not only against plant fungal pathogens but also against human fungal pathogens Aspergillus fumigatus and Candida albicans, Cryptococcus neoformans, and the model filamentous fungus Aspergillus nidulans. More importantly, toxoflavin also displays an efficacious inhibitory effect against azole antifungal-resistant mutants of A. fumigatus. Consequently, our findings provide a promising approach to abundantly produce toxoflavin, which has novel broad-spectrum antifungal activity, especially against those currently problematic drugresistant isolates.

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“…In fact, toxoflavin was known to be produced by B. gladioli (32), B. glumae (50,51), Pseudomonas protegens (52), and Streptomyces spp. (53).…”

Section: Discussionmentioning

confidence: 99%

“…LB and King's B medium (KMB) have been routinely used for toxoflavin production of Burkholderia spp. (30)(31)(32). Thus, LB medium and KMB was chosen for further testing.…”

mentioning

confidence: 99%

Toxoflavin Produced by Burkholderia gladioli from Lycoris aurea Is a New Broad-Spectrum Fungicide

Ren

et al. 2019

Appl Environ Microbiol

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“…As might be expected for a key virulence factor, regulation of toxA‐E and toxF‐I is under tight control in B. glumae , being independently influenced both by the TofIR quorum‐sensing (QS) system and by QS‐independent pathways (see below). Intriguingly, different strains of Burkholderia gladioli have been shown to differ in their ability to produce toxoflavin, despite carriage of intact toxABCDE and toxFGHI operons on the chromosomes (Lee et al ., ). The production of toxin in a toxoflavin‐negative strain of B. gladioli (KACC11889) could be restored by expression of the tofIMR genes of B. glumae or B. gladioli BSR3 (Lee et al ., ).…”

Section: Established and Proposed Virulence Factorsmentioning

confidence: 97%

“…Intriguingly, different strains of Burkholderia gladioli have been shown to differ in their ability to produce toxoflavin, despite carriage of intact toxABCDE and toxFGHI operons on the chromosomes (Lee et al ., ). The production of toxin in a toxoflavin‐negative strain of B. gladioli (KACC11889) could be restored by expression of the tofIMR genes of B. glumae or B. gladioli BSR3 (Lee et al ., ). These toxoflavin‐restored strains inflicted a greater degree of damage to host plants than the parental KACC11889 strain.…”

Section: Established and Proposed Virulence Factorsmentioning

confidence: 97%

Functional and genomic insights into the pathogenesis of Burkholderia species to rice

Naughton

Hwang

et al. 2016

Environmental Microbiology

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SummaryA number of species of bacteria from the genus Burkholderia have been shown to be causal agents of diseases of rice. These diseases, caused by Burkholderia glumae, B. gladioli and B. plantarii, are becoming increasingly common across the globe. This is particularly so for B. glumae, whose ability to grow at elevated temperatures suggests that it may become a prevalent problem in an era of global warming. Despite the increasing threat to rice, relatively little is known about the virulence mechanisms employed by these pathogens. Work over the last 5 years has provided an increasing insight into these factors and their control by environmental and other cues. In addition, the determination of a number of genome sequences has allowed bioinformatic predictions of further possible mechanisms, which can now be investigated experimentally. Here, we review recent advances in the understanding of virulence of Burkholderia to rice, to include discussion of the roles of toxins, type II secreted enzymes, type III secreted effectors and motility as well as their regulation by quorum sensing, two-component systems and cyclic di-GMP signalling. Finally, we consider a number of approaches for the control of bacterial virulence through the modulation of quorum sensing and toxin degradation.

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“…According to the phylogenetic analyses, this genus can be divided into two large clusters, in spited of its wide range, including the cluster of plant or human pathogens, and the cluster of plant-associated species pathogens (Estrada-de los Santos et al, 2013; Weisskopf et al, 2011). Of the plant pathogens, two species B. glumae and B. gladioli are emergent agents that cause serious diseases on rice, such as seedling blight, panicle blight, grain rot, and sheath rot, resulting in heavy yield losses in many countries worldwide (Ham et al, 2011; Lee et al, 2016; Nandakumar et al, 2009; Ura et al, 2006). While B. pseudomallei and B. cepacia have been well-known as important representative species of human pathogens because they are opportunistic pathogens that are common agents of hospital-associated infections, which act by repressing the immune system of animals and humans, causing melioidosis (by B. pseudomallei ) and cystic fibrosis disease (by B. cepacia ) (Govan and Deretic, 1996; Wiersinga et al, 2006).…”

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confidence: 99%

Computational Identification and Comparative Analysis of Secreted and Transmembrane Proteins in Six Burkholderia Species

Nguyen

Lee

Park

et al. 2017

The Plant Pathology Journal

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As a step towards discovering novel pathogenesis-related proteins, we performed a genome scale computational identification and characterization of secreted and transmembrane (TM) proteins, which are mainly responsible for bacteria-host interactions and interactions with other bacteria, in the genomes of six representative Burkholderia species. The species comprised plant pathogens (B. glumae BGR1, B. gladioli BSR3), human pathogens (B. pseudomallei K96243, B. cepacia LO6), and plant-growth promoting endophytes (Burkholderia sp. KJ006, B. phytofirmans PsJN). The proportions of putative classically secreted proteins (CSPs) and TM proteins among the species were relatively high, up to approximately 20%. Lower proportions of putative type 3 non-classically secreted proteins (T3NCSPs) (~10%) and unclassified non-classically secreted proteins (NCSPs) (~5%) were observed. The numbers of TM proteins among the three clusters (plant pathogens, human pathogens, and endophytes) were different, while the distribution of these proteins according to the number of TM domains was conserved in which TM proteins possessing 1, 2, 4, or 12 TM domains were the dominant groups in all species. In addition, we observed conservation in the protein size distribution of the secreted protein groups among the species. There were species-specific differences in the functional characteristics of these proteins in the various groups of CSPs, T3NCSPs, and unclassified NCSPs. Furthermore, we assigned the complete sets of the conserved and unique NCSP candidates of the collected Burkholderia species using sequence similarity searching. This study could provide new insights into the relationship among plant-pathogenic, human-pathogenic, and endophytic bacteria.

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Differential regulation of toxoflavin production and its role in the enhanced virulence of Burkholderia gladioli

Cited by 51 publications

References 44 publications

Toxoflavin Produced by Burkholderia gladioli from Lycoris aurea Is a New Broad-Spectrum Fungicide

Toxoflavin Produced by Burkholderia gladioli from Lycoris aurea Is a New Broad-Spectrum Fungicide

Functional and genomic insights into the pathogenesis of Burkholderia species to rice

Computational Identification and Comparative Analysis of Secreted and Transmembrane Proteins in Six Burkholderia Species

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