Unexpected Bacterial Origin of the Antibiotic Icosalide: Two-Tailed Depsipeptide Assembly in Multifarious <i>Burkholderia</i> Symbionts

Dose, Benjamin; Niehs, Sarah P.; Scherlach, Kirstin; Flórez, Laura; Kaltenpoth, Martin; Hertweck, Christian

doi:10.1021/acschembio.8b00600

Cited by 66 publications

(72 citation statements)

References 36 publications

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“…3). Two of these have been putatively assigned to production of the antibiotic lagriene in Lv-StA (Flórez et al, 2017), and the antifungal lagriamide in Lv-StB (Flórez et al, 2018), whereas five other small molecules known to be produced by Lv-StA have been assigned to shorter BGCs (Dose et al, 2018; Flórez et al, 2017). That 15 out of the 17 largest assembled BGCs remain without characterized products suggests that the majority of biosynthetic pathways in the L. villosa egg microbiome likely codes for novel small molecule products.…”

Section: Resultsmentioning

confidence: 99%

“…Schematics of all BGCs with greater than 50 kbp length assembled from the L. villosa metagenome and in the B. gladioli Lv-StA isolate genome, out of 126 identified by antiSMASH (left). Shown on the right are structures of compounds putatively assigned to BGCs in the B. gladioli Lv-StA genome (Dose et al, 2018; Flórez et al, 2017), or putatively assigned to a BGC in the Burkholderia Lv-StB genome (Flórez et al, 2018). Structures highlighted with red symbols have been attributed to the indicated BGCs.…”

Section: Resultsmentioning

confidence: 99%

“…In the species Lagria villosa , a South American soybean pest, at least one symbiotic B. gladioli strain (Lv-StA) has been cultured and is still capable of infecting plants (Flórez et al, 2017). The same strain produces antibacterial and antifungal compounds that can protect the beetle’s eggs from infection (Dose et al, 2018; Flórez et al, 2017). This is consistent with the hypothesis that the B. gladioli symbionts evolved from plant pathogens to become beetle mutualists.…”

Section: Introductionmentioning

confidence: 99%

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Horizontal gene transfer to a defensive symbiont with a reduced genome amongst a multipartite beetle microbiome

Waterworth¹,

Flórez

Rees³

et al. 2019

Preprint

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19The loss of functions required for independent life when living within a host gives rise to 20 reduced genomes in obligate bacterial symbionts. Although this phenomenon can be 21 explained by existing evolutionary models, its initiation is not well understood. Here, we 22 32 33 38 Kroiss et al., 2010). Such relationships exist on a continuous spectrum of dependency 39 and exclusivity from the perspective of both the host and symbiont. Symbionts generally 40 become obligate after a prolonged period of exclusive association with the host, and the 41 3 symbionts that become obligate tend to carry out highly important functions for the host 42 (Latorre and Manzano-Marín, 2017; Lo et al., 2016; McCutcheon and Moran, 2012). For 43 example, mitochondria and chloroplasts, organelles that are required for energy 44 production and carbon fixation in eukaryotic and plant cells, originated from 45 endosymbiotic capture of alphaproteobacteria and cyanobacteria ~1.2 Bya and ~900 46

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Horizontal gene transfer to a defensive symbiont with a reduced genome amongst a multipartite beetle microbiome

Waterworth¹,

Flórez

Rees³

et al. 2019

Preprint

Self Cite

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“…For the identification of natural products, Bacillus sp. strain D121-0906-b3-2-1 was inoculated in diverse media (MGY+M9 66 and soy mannit medium + CESE) at OD600 0.1 and grown at 160 rpm, 28 °C for 3-8 days. Extraction took place with 1:1 volume of ethyl acetate overnight or with addition of XAD-2 to the culture broth for 30 minutes followed by elution twice with 100% methanol for 30 minutes.…”

Section: Secondary Metabolite Productionmentioning

confidence: 99%

Highly parallelized microfluidic droplet cultivation and prioritization on antibiotic producers from complex natural microbial communities

Mahler

Niehs

Martin

et al. 2019

Preprint

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To investigate the overwhelming part of the bacterial diversity still evading standard cultivation for its potential use in antibiotic synthesis, we have compiled a microscale-cultivation and screening system.We devised a strategy based on droplet-microfluidics taking advantage of the inherent miniaturization and high throughput. Single cells of natural samples were confined in 9 x 10 6 aqueous droplets and subjected to long-term incubation under controlled conditions. Subsequent a high-throughput screening for antimicrobial natural products was implemented, employing a whole cell reporting system using the viability of reporter strains as a probe for antimicrobial activity. Due to the described microscale cultivation a novel subset of bacterial strains was made available for the following screening for antimicrobials. We demonstrate the merits of the in-droplet cultivation by comparing the cultivation outcome in microfluidic droplets and on conventional agar plates for a bacterial community derived from soil by 16S rRNA gene amplicon sequencing. In-droplet cultivation resulted in a significantly higher bacterial diversity without the common overrepresentation of Firmicutes. Natural strains able to inhibit either a Gram-positive or a Gram-negative reporter strain were isolated from the microscale system and further cultivated. Thereby a variety of rare isolates was obtained. The natural products with antimicrobial activity were elucidated for the most promising candidate. Our method combines a new cultivation approach with a high-throughput search for antibiotic producers to increase the chances of finding new lead substances.

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“…These include gladiolin, a novel macrolide with potent activity against drug resistant Mycobacterium tuberculosis clinical isolates, 23 and icosalide A1, 34 an asymmetric lipopeptodiolide antibiotic originally isolated from an Aureobasidium species fungus, 35 but subsequently shown to be produced by various strains of B. gladioli including one associated with the fungus. 34,36 Analysis of the B. gladioli BCC0238 complete genome sequence identified several gene clusters encoding cryptic nonribosomal peptide synthetase (NRPS), polyketide synthase (PKS) and hybrid NRPS-PKS assembly lines. 21 Here we report the discovery of gladiochelins A and B, novel lipodepsipeptides containing a unique citrate-derived fatty acid and a rare dehydro--alanine residue, as the metabolic products of one of these gene clusters.…”

Section: Introductionmentioning

confidence: 99%

Discovery and biosynthesis of gladiochelins: unusual lipodepsipeptide siderophores fromBurkholderia gladioli

Dashti

Nakou

Mullins

et al. 2020

Preprint

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Burkholderia is a genus of diverse Gram-negative bacteria that includes several opportunistic pathogens. Siderophores, which transport iron from the environment into microbial cells, are important virulence factors in most pathogenic Burkholderia species. However, it is widely believed that Burkholderia gladioli, which can infect the lungs of cystic fibrosis (CF) sufferers, does not produce siderophores. B. gladioli BCC0238, isolated from the lung of a CF patient, produces two novel metabolites in a minimal medium containing glycerol and ribose as carbon sources. HPLC purification, followed by detailed spectroscopic analyses, identified these metabolites as unusual lipodepsipeptides containing a unique citrate-derived fatty acid and a rare dehydro-β-alanine residue. The absolute configurations of the amino acid residues in the two metabolites was elucidated using Marfey's method and the gene cluster responsible for their biosynthesis was identified by bioinformatics and insertional mutagenesis. In-frame deletions and enzyme activity assays were used to investigate the functions of several proteins encoded by the biosynthetic gene cluster, which was found in the genomes of most B. gladioli isolates, suggesting that its metabolic products play an important role in the growth and/or survival of the species. The Chrome Azurol S (CAS) assay showed the metabolites bind ferric iron and that this supresses their production when added to the growth medium. Moreover, a gene encoding a TonB-dependent ferric-siderophore receptor is adjacent to the biosynthetic genes. Together, these observations suggest that these metabolites likely function as siderophores in B. gladioli.

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Unexpected Bacterial Origin of the Antibiotic Icosalide: Two-Tailed Depsipeptide Assembly in Multifarious Burkholderia Symbionts

Cited by 66 publications

References 36 publications

Horizontal gene transfer to a defensive symbiont with a reduced genome amongst a multipartite beetle microbiome

Horizontal gene transfer to a defensive symbiont with a reduced genome amongst a multipartite beetle microbiome

Highly parallelized microfluidic droplet cultivation and prioritization on antibiotic producers from complex natural microbial communities

Discovery and biosynthesis of gladiochelins: unusual lipodepsipeptide siderophores fromBurkholderia gladioli

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