Burkholderia as a Source of Natural Products

Abstract

Burkholderia bacteria are multifaceted organisms that are ecologically and metabolically diverse. The Burkholderia genus has gained prominence because it includes human pathogens; however, many strains are nonpathogenic and have desirable characteristics such as beneficial plant associations and degradation of pollutants. The diversity of the Burkholderia genus is reflected within the large genomes that feature multiple replicons. Burkholderia genomes encode a plethora of natural products with potential therapeutic relevance and biotechnological applications. This review highlights Burkholderia as an emerging source of natural products. An overview of the taxonomy of the Burkholderia genus, which is currently being revised, is provided. We then present a curated compilation of natural products isolated from Burkholderia sensu lato and analyze their characteristics in terms of biosynthetic class, discovery method, and bioactivity. Finally, we describe and discuss genome characteristics and highlight the biosynthesis of a select number of natural products that are encoded in unusual biosynthetic gene clusters. The availability of >1000 Burkholderia genomes in public databases provides an opportunity to realize the genetic potential of this underexplored taxon for natural product discovery.

Figure 1.

Overview of Burkholderia sensu lato, its ecological roles and potential applications. Members of Burkholderia sensu lato occupy diverse ecological niches ranging from pristine soil and aquatic environments to contaminated landfill, and they can be free-living or associated with a wide set of eukaryotic hosts, from fungi to humans. Host associations can be harmful (e.g. human and animal pathogens that include biological warfare agents) or beneficial (e.g. endosymbionts that promote plant growth). Ecological niche diversity translates into diverse natural products that mediate host interactions, that are beneficial for adaptation and survival, and that may be harnessed for biotechnological applications and drug discovery.

Figure 2.

Analysis of natural products isolated from Burkholderia sensu lato. (A) Pie chart depicting biosynthetic class. Compounds belonging to the same structural class (defined as known or expected to be encoded in the same or very similar BGC) were counted as one. The 66 structural classes (corresponding to 66 cells in Figure 3) were then classified into seven biosynthetic classes as shown. Compounds that did not belong to any of the seven classes or for which the biosynthesis was unknown were classified as “other/unknown”. (B) Natural product identification method. “Other” includes structure-guided isolation. (C) Reported bioactivity. If a compound displayed more than one bioactivity, they were categorized as follows: Cytotoxic compounds that had more than one bioactivity were counted as “cytotoxic” only. Antitumor and anticancer compounds were also included under cytotoxic. Compounds that had antifungal and antibacterial activity were added to one of the two categories based on highest displayed potency. Activities that did not fit within the depicted groups were designated as “other”, which includes phosphodiesterase 4 inhibitor, Gq-signaling inhibitor, vasopressin and serotonin receptor interacting, plant growth inhibitor, ethylene biosynthesis inhibitor, virulence, and quorum sensing signal.

Figure 3.

Natural products isolated from Burkholderia sensu lato. Compounds are grouped and color-coded based on biosynthetic class as in Figure 2A. The bacterial source (B., Burkholderia, P., Paraburkholderia), discovery method, reported bioactivity, and references are indicated. For the “other/unknown” category, the biosynthesis is either not yet elucidated or the biosynthetic class does not belong in the categories depicted. In cases where many congeners of a compound class have been isolated, only representative examples are shown. Note that B. rhizoxinica and B. endofungorum as the reported sources of rhizomide A, heptarhizin, holrhizin A, WF-1360F, burhizin, and rhizonins were later revised as P. rhizoxinica and P. endofungorum and most recently transferred to the new genus Mycetohabitans. *Denotes that chemical structure was not fully elucidated or that the compound was detected by mass spectrometry only, in which cases we opted to not show the proposed structure with the exception of N-acylhomoserine lactones.

Figure 3.

Natural products isolated from Burkholderia sensu lato. Compounds are grouped and color-coded based on biosynthetic class as in Figure 2A. The bacterial source (B., Burkholderia, P., Paraburkholderia), discovery method, reported bioactivity, and references are indicated. For the “other/unknown” category, the biosynthesis is either not yet elucidated or the biosynthetic class does not belong in the categories depicted. In cases where many congeners of a compound class have been isolated, only representative examples are shown. Note that B. rhizoxinica and B. endofungorum as the reported sources of rhizomide A, heptarhizin, holrhizin A, WF-1360F, burhizin, and rhizonins were later revised as P. rhizoxinica and P. endofungorum and most recently transferred to the new genus Mycetohabitans. *Denotes that chemical structure was not fully elucidated or that the compound was detected by mass spectrometry only, in which cases we opted to not show the proposed structure with the exception of N-acylhomoserine lactones.

Figure 3.

Natural products isolated from Burkholderia sensu lato. Compounds are grouped and color-coded based on biosynthetic class as in Figure 2A. The bacterial source (B., Burkholderia, P., Paraburkholderia), discovery method, reported bioactivity, and references are indicated. For the “other/unknown” category, the biosynthesis is either not yet elucidated or the biosynthetic class does not belong in the categories depicted. In cases where many congeners of a compound class have been isolated, only representative examples are shown. Note that B. rhizoxinica and B. endofungorum as the reported sources of rhizomide A, heptarhizin, holrhizin A, WF-1360F, burhizin, and rhizonins were later revised as P. rhizoxinica and P. endofungorum and most recently transferred to the new genus Mycetohabitans. *Denotes that chemical structure was not fully elucidated or that the compound was detected by mass spectrometry only, in which cases we opted to not show the proposed structure with the exception of N-acylhomoserine lactones.

Figure 3.

Natural products isolated from Burkholderia sensu lato. Compounds are grouped and color-coded based on biosynthetic class as in Figure 2A. The bacterial source (B., Burkholderia, P., Paraburkholderia), discovery method, reported bioactivity, and references are indicated. For the “other/unknown” category, the biosynthesis is either not yet elucidated or the biosynthetic class does not belong in the categories depicted. In cases where many congeners of a compound class have been isolated, only representative examples are shown. Note that B. rhizoxinica and B. endofungorum as the reported sources of rhizomide A, heptarhizin, holrhizin A, WF-1360F, burhizin, and rhizonins were later revised as P. rhizoxinica and P. endofungorum and most recently transferred to the new genus Mycetohabitans. *Denotes that chemical structure was not fully elucidated or that the compound was detected by mass spectrometry only, in which cases we opted to not show the proposed structure with the exception of N-acylhomoserine lactones.

Figure 3.

Natural products isolated from Burkholderia sensu lato. Compounds are grouped and color-coded based on biosynthetic class as in Figure 2A. The bacterial source (B., Burkholderia, P., Paraburkholderia), discovery method, reported bioactivity, and references are indicated. For the “other/unknown” category, the biosynthesis is either not yet elucidated or the biosynthetic class does not belong in the categories depicted. In cases where many congeners of a compound class have been isolated, only representative examples are shown. Note that B. rhizoxinica and B. endofungorum as the reported sources of rhizomide A, heptarhizin, holrhizin A, WF-1360F, burhizin, and rhizonins were later revised as P. rhizoxinica and P. endofungorum and most recently transferred to the new genus Mycetohabitans. *Denotes that chemical structure was not fully elucidated or that the compound was detected by mass spectrometry only, in which cases we opted to not show the proposed structure with the exception of N-acylhomoserine lactones.

Figure 3.

Natural products isolated from Burkholderia sensu lato. Compounds are grouped and color-coded based on biosynthetic class as in Figure 2A. The bacterial source (B., Burkholderia, P., Paraburkholderia), discovery method, reported bioactivity, and references are indicated. For the “other/unknown” category, the biosynthesis is either not yet elucidated or the biosynthetic class does not belong in the categories depicted. In cases where many congeners of a compound class have been isolated, only representative examples are shown. Note that B. rhizoxinica and B. endofungorum as the reported sources of rhizomide A, heptarhizin, holrhizin A, WF-1360F, burhizin, and rhizonins were later revised as P. rhizoxinica and P. endofungorum and most recently transferred to the new genus Mycetohabitans. *Denotes that chemical structure was not fully elucidated or that the compound was detected by mass spectrometry only, in which cases we opted to not show the proposed structure with the exception of N-acylhomoserine lactones.

Figure 4.

Genome maps of representative Burkholderia species highlighting their multi-replicon nature and the distribution of biosynthetic gene clusters. (A) Burkholderia cepacia ATCC 25416 (accession codes: NZ_CP012981, NZ_CP012982, NZ_CP012983 and NZ_CP012984 for chromosomes 1 and 2 and plasmids 1 and 2, respectively). Megaplasmid 1 has also been referred to as chromosome 3. Plasmid 2 was named pBC25416. (B) Burkholderia pseudomallei K96243 (accession codes: NC_006350 and NC_006351 for chromosomes 1 and 2, respectively). (C) Paraburkholderia xenovorans LB400 (accession codes: NC_007951, NC_007952 and NC_007953 for chromosomes 1 and 2 and plasmid). The megaplasmid has also been termed chromosome 3. In all cases, chromosome 1 is oriented to dnaA and chromosome 2 to parA. Plasmids are oriented to parB or parA-like proteins. The location of biosynthetic gene clusters for natural products is indicated and color-coded by biosynthetic class as shown (lane 1 from the outside in). Predicted open reading frames (ORFs) on the leading (black) and lagging (gray) strands are shown on lanes 2 and 3, respectively. A normalized plot of guanosine + cytosine (G+C) content (blue/purple) is depicted in lane 4.

Figure 5.

Biosynthesis of malleilactone and burkholderic acid by B. pseudomallei, B. mallei and B. thailandensis. The model shown is according to studies in B. thailandensis E264 described in references^,

Figure 6.

Biosynthesis of spliceostatins by Burkholderia sp. FERM BP-3421 and B. thailandensis MSMB43. The model shown is according to several lines of evidence described in references^,,, Module numbering is according to the current convention for trans-AT PKSs.

Figure 7.

Biosynthesis of rhizoxin. The model shown is according to several lines of evidence provided by references^,,,–