Epidemiology of <i>Burkholderia</i> Infections in People with Cystic Fibrosis in Canada between 2000 and 2017

Zlosnik, James E. A.; Henry, Deborah A.; Hird, Trevor J.; Hickman, Rebeccca; Campbell, Margaret A.; Cabrera, Adriana; Chiavegatti, Giulio Laino; Chilvers, Mark; Sadarangani, Manish

doi:10.1513/annalsats.201906-443oc

Cited by 13 publications

(12 citation statements)

References 42 publications

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“…14,16,17 These Bcc species are most associated with infections in CF patients. 18,19 Of the 12 Bcc strains tested, 6 were susceptible to ubonodin (Figures 1B and S1), and their levels of susceptibility were similar, ranging from 10 to 40 μM ubonodin in a plate-based spot assay (Table S1). Thus, ubonodin is selectively active against a subset of Bcc strains.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…We focused on strains from the Bcc because they are most closely related to the ubonodin producer, Burkholderia ubonensis, and RiPPs tend to have a focused spectrum of activity. , Moreover, we anticipated that the elusive genetic signatures differentiating ubonodin-susceptible (ubo S ) from non-susceptible (ubo N ) Bcc strains should be more apparent as Bcc members are otherwise highly similar. In total, we tested the activity of ubonodin against 12 Bcc strains representing 6 distinct Bcc species or genomovars. ,, These Bcc species are most associated with infections in CF patients. , Of the 12 Bcc strains tested, 6 were susceptible to ubonodin (Figures B and S1), and their levels of susceptibility were similar, ranging from 10 to 40 μM ubonodin in a plate-based spot assay (Table S1). Thus, ubonodin is selectively active against a subset of Bcc strains.…”

Section: Resultsmentioning

confidence: 99%

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Phenotype-Guided Comparative Genomics Identifies the Complete Transport Pathway of the Antimicrobial Lasso Peptide Ubonodin in Burkholderia

Thokkadam

Leach

et al. 2022

ACS Chem. Biol.

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New antibiotics are needed as bacterial infections continue to be a leading cause of death, but efforts to develop compounds with promising antibacterial activity are hindered by a poor understanding ofand limited strategies for elucidatingtheir modes of action. We recently discovered a novel lasso peptide, ubonodin, that is active against opportunistic human lung pathogens from the Burkholderia cepacia complex (Bcc). Ubonodin inhibits RNA polymerase, but only select strains were susceptible, indicating that having a conserved cellular target does not guarantee activity. Given the cytoplasmic target, we hypothesized that cellular uptake of ubonodin determines susceptibility. Although Bcc strains harbor numerous nutrient uptake systems, these organisms lack close homologues of the single known lasso peptide membrane receptor, FhuA. Thus, a straightforward homology-driven approach failed to uncover the identity of the ubonodin transporter(s). Here, we used phenotype-guided comparative genomics to identify genes uniquely associated with ubonodin-susceptible Bcc strains, leading to the identification of PupB as the ubonodin outer membrane (OM) receptor in Burkholderia. The loss of PupB renders B. cepacia resistant to ubonodin, whereas expressing PupB sensitizes a resistant strain. We also examine how a conserved iron-regulated transcriptional pathway controls PupB to further tune ubonodin susceptibility. PupB is only the second lasso peptide OM receptor to be uncovered and the first outside of enterobacteria. Finally, we elucidate the full transport pathway for ubonodin by identifying its inner membrane receptor YddA in Burkholderia. Our work provides a complete picture of the mode of action of ubonodin and establishes a general framework for deciphering the transport pathways of other natural products with cytoplasmic targets.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Phenotype-Guided Comparative Genomics Identifies the Complete Transport Pathway of the Antimicrobial Lasso Peptide Ubonodin in Burkholderia

Thokkadam

Leach

et al. 2022

ACS Chem. Biol.

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“…In total, we tested the activity of ubonodin against 12 Bcc strains representing 6 distinct Bcc species or genomovars, including several Bcc strains that were recommended for genetic studies (Coenye et al, 2001; Depoorter et al, 2020; Mahenthiralingam et al, 2000). These Bcc species are also most associated with infections in CF patients (LiPuma, 2010; Zlosnik et al, 2020). Of the 12 Bcc strains tested, 6 were susceptible to ubonodin ( Figure 2 and Figure 2 – figure supplement 1 ).…”

Section: Resultsmentioning

confidence: 99%

The Anti-Burkholderia Lasso Peptide Ubonodin Co-Opts the Siderophore Receptor PupB for Cellular Entry

Thokkadam

Leach

et al. 2022

Preprint

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New antibiotics are needed as bacterial infections continue to be a leading cause of death. Notorious among antibiotic-resistant bacteria is the Burkholderia cepacia complex (Bcc), which infects cystic fibrosis patients, causing lung function decline. We recently discovered a novel ribosomally synthesized and post-translationally modified peptide (RiPP), ubonodin, with potent activity against several Burkholderia pathogens. Ubonodin inhibits RNA polymerase, but only select Bcc strains were susceptible, indicating that having a conserved cellular target does not guarantee activity. Given the cytoplasmic target, we speculate that cellular uptake of ubonodin determines susceptibility. Here, we report a new outer membrane siderophore receptor, PupB, that is required for ubonodin uptake in B. cepacia. Loss of PupB renders B. cepacia resistant to ubonodin, whereas expressing PupB sensitizes a resistant strain. Thus, outer membrane transport is the major determinant of ubonodin’s spectrum of activity. We also show that PupB is activated by a TonB protein and examine a transcriptional pathway that further regulates PupB. Finally, we elucidate the complete cellular uptake pathway for ubonodin by also identifying its inner membrane transporter in B. cepacia. Our work unravels central steps in the mechanism of action of ubonodin and establishes a general framework for dissecting RiPP function.

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“…2 ), a recent Canadian study demonstrated profound epidemiological shifts within this range, with a significant decline in the limited numbers of epidemic B. cenocepacia strains more recently being replaced with the increasing prevalence of nonclonal isolates of B. multivorans and other species. 99 B. cenocepacia , in particular, have been associated with more severe lung disease including rapid respiratory decline and increased overall mortality. 100 While uncommon and very rare in recent years, rapidly progressive necrotizing pneumonia with or without refractory bacteremia termed “cepacia syndrome” from (predominately) B. cenocepacia has been associated with near-uniform fatality.…”

Section: Traditional Landscape Of Cystic Fibrosis Airway Infections: ...mentioning

confidence: 99%

Microbial Epidemiology of the Cystic Fibrosis Airways: Past, Present, and Future

Thornton

Parkins

2023

Semin Respir Crit Care Med

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Progressive obstructive lung disease secondary to chronic airway infection, coupled with impaired host immunity, is the leading cause of morbidity and mortality in cystic fibrosis (CF). Classical pathogens found in the airways of persons with CF (pwCF) include Pseudomonas aeruginosa, Staphylococcus aureus, the Burkholderia cepacia complex, Achromobacter species, and Haemophilus influenzae. While traditional respiratory-tract surveillance culturing has focused on this limited range of pathogens, the use of both comprehensive culture and culture-independent molecular approaches have demonstrated complex highly personalized microbial communities. Loss of bacterial community diversity and richness, counteracted with relative increases in dominant taxa by traditional CF pathogens such as Burkholderia or Pseudomonas, have long been considered the hallmark of disease progression. Acquisition of these classic pathogens is viewed as a harbinger of advanced disease and postulated to be driven in part by recurrent and frequent antibiotic exposure driven by frequent acute pulmonary exacerbations. Recently, CF transmembrane conductance regulator (CFTR) modulators, small molecules designed to potentiate or restore diminished protein levels/function, have been successfully developed and have profoundly influenced disease course. Despite the multitude of clinical benefits, structural lung damage and consequent chronic airway infection persist in pwCF. In this article, we review the microbial epidemiology of pwCF, focus on our evolving understanding of these infections in the era of modulators, and identify future challenges in infection surveillance and clinical management.

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Epidemiology of Burkholderia Infections in People with Cystic Fibrosis in Canada between 2000 and 2017

Cited by 13 publications

References 42 publications

Phenotype-Guided Comparative Genomics Identifies the Complete Transport Pathway of the Antimicrobial Lasso Peptide Ubonodin in Burkholderia

Phenotype-Guided Comparative Genomics Identifies the Complete Transport Pathway of the Antimicrobial Lasso Peptide Ubonodin in Burkholderia

The Anti-Burkholderia Lasso Peptide Ubonodin Co-Opts the Siderophore Receptor PupB for Cellular Entry

Microbial Epidemiology of the Cystic Fibrosis Airways: Past, Present, and Future

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