Correction to Global Awakening of Cryptic Biosynthetic Gene Clusters in <i>Burkholderia thailandensis</i>

Gupta, Ashish; Bedre, Renesh; Thapa, Sudarshan Singh; Sabrin, Afsana; Wang, Guannan; Dassanayake, Maheshi; Grove, Anne

doi:10.1021/acschembio.7b01056

Cited by 3 publications

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“…Combined, these factors would work to reduce the xanthine concentration within the cell. We also note that malR and malA expression is increased 2.5-fold and 5-fold, respectively, based on RNA-seq data on exposure to 5 mM of the also poorly soluble and readily metabolizable urate, levels of induction that are comparable to those seen here with xanthine, and that equivalent urate-mediated increases in gene expression are not observed in ΔmftR cells (Gupta et al, 2017). Taken together, our results indicate that xanthine accumulation may contribute to the increased expression of malR and malA on exposure to trimethoprim and that it may do so, at least in part, by acting as a ligand for MftR.…”

Section: Xanthine Accumulates In Cells Grown With Trimethoprimsupporting

confidence: 69%

“…We have previously reported that urate elicits an upregulation of malR and the mal gene cluster, suggesting the possibility that the changes in purine homeostasis expected on treatment with trimethoprim include elevated urate levels (Gupta et al, 2017). While…”

Section: Xanthine Accumulates In Cells Grown With Trimethoprimmentioning

confidence: 99%

“…This raises the possibility that MftR participates in controlling gene expression in response to accumulation of intracellular xanthine. The gene encoding MftR is divergent to mftP, which encodes the efflux pump MftP; MftR binds the mftR-mftP intergenic region, causing repression of both genes, and urate induces expression of mftP in a concentration-dependent manner, with increased expression observed when ≥5 mM urate was added to the media (Gupta et al, 2017). Accordingly, we would expect upregulation of mftP only if intracellular xanthine levels reach a certain threshold.…”

Section: F I G U R Ementioning

confidence: 99%

“…The transcription factor MftR controls expression of ~400 genes in B. thailandensis, and its DNA binding is attenuated on binding of the ligands urate or xanthine (Grove, 2010;Gupta et al, 2017). This raises the possibility that MftR participates in controlling gene expression in response to accumulation of intracellular xanthine.…”

Section: F I G U R Ementioning

confidence: 99%

“…In general, MftR functions as a repressor as 331 of these genes are upregulated in an mftR knockout mutant. These include genes involved in metabolic pathways, production of secondary metabolites, and virulence (Gupta et al, 2017). Interestingly, the secondary metabolites that accumulate in B. thailandensis under the effect of trimethoprim correspond strikingly to genes that are upregulated when the MftR ligand urate is added to the growth media.…”

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confidence: 99%

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Impaired purine homeostasis plays a primary role in trimethoprim‐mediated induction of virulence genes in Burkholderia thailandensis

Thapa

Grove

2020

Molecular Microbiology

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The genus Burkholderia comprises about 100 species, which occupy diverse ecological niches (free living, saprophytic, obligate endosymbionts, phytopathogens, opportunistic pathogens, or obligate parasites). Some of these species have potential for use as bioremediation or biocontrol agents, but the genus is primarily known for the pathogenic strains, namely B. pseudomallei, B. mallei, and the closely related B. cepacia complex (Bcc) species (Compant et al., 2008; Eberl and Vandamme, 2016). B. thailandensis is a relatively nonpathogenic strain, which has been used as a model to study mechanisms of gene regulation and virulence in B. pseudomallei and B. mallei. Due to high genetic similarity between these species, they have been classified together as the Burkholderia pseudomallei complex (Bpc) (Gupta et al., 2019;Sahl et al., 2016). B. pseudomallei and B. mallei cause melioidosis and glanders, respectively, potentially fatal diseases

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Section: Xanthine Accumulates In Cells Grown With Trimethoprimsupporting

confidence: 69%

Section: Xanthine Accumulates In Cells Grown With Trimethoprimmentioning

confidence: 99%

Section: F I G U R Ementioning

confidence: 99%

Section: F I G U R Ementioning

confidence: 99%

mentioning

confidence: 99%

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Impaired purine homeostasis plays a primary role in trimethoprim‐mediated induction of virulence genes in Burkholderia thailandensis

Thapa

Grove

2020

Molecular Microbiology

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The NarX-NarL two-component system regulates biofilm formation, natural product biosynthesis, and host-associated survival in Burkholderia pseudomallei

Mangalea

Borlee

2022

Sci Rep

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Burkholderia pseudomallei is a saprophytic bacterium endemic throughout the tropics causing severe disease in humans and animals. Environmental signals such as the accumulation of inorganic ions mediates the biofilm forming capabilities and survival of B. pseudomallei. We have previously shown that B. pseudomallei responds to nitrate and nitrite by inhibiting biofilm formation and altering cyclic di-GMP signaling. To better understand the roles of nitrate-sensing in the biofilm inhibitory phenotype of B. pseudomallei, we created in-frame deletions of narX (Bp1026b_I1014) and narL (Bp1026b_I1013), which are adjacent components of a conserved nitrate-sensing two-component system. We observed transcriptional downregulation in key components of the biofilm matrix in response to nitrate and nitrite. Some of the most differentially expressed genes were nonribosomal peptide synthases (NRPS) and/or polyketide synthases (PKS) encoding the proteins for the biosynthesis of bactobolin, malleilactone, and syrbactin, and an uncharacterized cryptic NRPS biosynthetic cluster. RNA expression patterns were reversed in ∆narX and ∆narL mutants, suggesting that nitrate sensing is an important checkpoint for regulating the diverse metabolic changes occurring in the biofilm inhibitory phenotype. Moreover, in a macrophage model of infection, ∆narX and ∆narL mutants were attenuated in intracellular replication, suggesting that nitrate sensing contributes to survival in the host.

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The NarX-NarL two-component system is a global regulator of biofilm formation, natural product biosynthesis, and host-associated survival inBurkholderia pseudomallei

Borlee

Mangalea

2020

Preprint

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In the environment, Burkholderia pseudomallei exists as a saprophyte inhabiting soils and surface waters where denitrification is important for anaerobic respiration. As an opportunistic pathogen, B. pseudomallei transitions from the environment to infect human and animal hosts where respiratory nitrate reduction enables replication in anoxic conditions. We have previously shown that B. pseudomallei responds to nitrate and nitrite in part by inhibiting biofilm formation and altering cyclic di-GMP signaling. Here, we describe the global transcriptomic response to nitrate and nitrite to characterize the nitrosative stress response relative to biofilm inhibition. To better understand the roles of nitrate-sensing in the biofilm inhibitory phenotype of B. pseudomallei, we created in-frame deletions of narX (Bp1026b_I1014) and narL (Bp1026b_I1013), which are adjacent components of the conserved nitrate-sensing two-component system. Through differential expression analysis of RNA-seq data, we observed that key components of the biofilm matrix are downregulated in response to nitrate and nitrite. In addition, several gene loci associated with the stringent response, central metabolism dysregulation, antibiotic tolerance, and pathogenicity determinants were significantly altered in their expression. Some of the most differentially expressed genes were nonribosomal peptide synthases (NRPS) and/or polyketide synthases (PKS) encoding the proteins for the biosynthesis of bactobolin, malleilactone, and syrbactin, in addition to an uncharacterized cryptic NRPS biosynthetic cluster. We also observed reduced expression of ribosomal structural and biogenesis loci, and gene clusters associated with translation and DNA replication, indicating modulation of growth rate and metabolism under nitrosative stress conditions. The differences in expression observed under nitrosative stress were reversed in narX and narL mutants, suggesting that nitrate sensing is an important checkpoint for regulating the diverse metabolic changes occurring in the biofilm inhibitory phenotype. Moreover, in a macrophage model of infection, narX and narL mutants were attenuated in intracellular replication, suggesting that nitrate sensing is important for host survival.Author SummaryBurkholderia pseudomallei is a saprophytic bacterium inhabiting soils and surface waters throughout the tropics causing severe disease in humans and animals. Environmental signals such as the accumulation of inorganic ions mediates the biofilm forming capabilities and survival of B. pseudomallei. In particular, nitrate metabolism inhibits B. pseudomallei biofilm formation through complex regulatory cascades that relay environmental cues to intracellular second messengers that modulate bacterial physiology. Nitrates are common environmental contaminants derived from artificial fertilizers and byproducts of animal wastes that can be readily reduced by bacteria capable of denitrification. In B. pseudomallei 1026b, biofilm dynamics are in part regulated by a gene pathway involved in nitrate sensing, metabolism, and transport. This study investigated the role of a two-component nitrate sensing system, NarX-NarL, in regulating gene expression, biofilm formation, and cellular invasion. Global gene expression analyses in the wild type, as compared to Δ narX and Δ narL mutant strains with nitrate or nitrite implicate the NarX-NarL system in the regulation of biofilm components as well as B. pseudomallei host-associated survival. This study characterizes a conserved nitrate sensing system that is important in environmental and host-associated contexts and aims to bridge a gap between these two important B. pseudomallei lifestyles.

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Correction to Global Awakening of Cryptic Biosynthetic Gene Clusters in Burkholderia thailandensis

Cited by 3 publications

References 0 publications

Impaired purine homeostasis plays a primary role in trimethoprim‐mediated induction of virulence genes in Burkholderia thailandensis

Impaired purine homeostasis plays a primary role in trimethoprim‐mediated induction of virulence genes in Burkholderia thailandensis

The NarX-NarL two-component system regulates biofilm formation, natural product biosynthesis, and host-associated survival in Burkholderia pseudomallei

The NarX-NarL two-component system is a global regulator of biofilm formation, natural product biosynthesis, and host-associated survival inBurkholderia pseudomallei

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