ClbP Is a Prototype of a Peptidase Subgroup Involved in Biosynthesis of Nonribosomal Peptides

Dubois, Damien; Baron, Olivier; Cougnoux, Antony; Delmas, Julien; Pradel, Nathalie; Boury, Michèle; Bouchon, Bernadette; Bringer, Marie-Agnès; Nougayrède, Jean-Philippe; Oswald, Éric; Bonnet, Richard

doi:10.1074/jbc.m111.221960

Cited by 97 publications

(137 citation statements)

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“…Carriage of the pks island is linked to long-term persistence in the gastrointestinal (GI) tract (9), and pks-bearing strains represent a high-virulence subset within the B2 group (6). The 54-kb pks island encodes nonribosomal peptide synthases, polyketide synthases, and hybrid synthases, in addition to accessory, tailoring, and editing enzymes; the clbA gene encodes a phosphopantetheinyl transferase required for colibactin synthesis, and clbP specifies a D-amino peptidase involved in colibactin maturation (10,11). The pks island also contributes to the synthesis of siderophores by virtue of the broad substrate specificity of ClbA, impacting iron acquisition and the ability to survive in the blood compartment (12).…”

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The Genotoxin Colibactin Is a Determinant of Virulence in Escherichia coli K1 Experimental Neonatal Systemic Infection

et al. 2015

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Escherichia coli strains expressing the K1 capsule are a major cause of sepsis and meningitis in human neonates. The development of these diseases is dependent on the expression of a range of virulence factors, many of which remain uncharacterized. Here, we show that all but 1 of 34 E. coli K1 neonatal isolates carried clbA and clbP, genes contained within the pks pathogenicity island and required for the synthesis of colibactin, a polyketide-peptide genotoxin that causes genomic instability in eukaryotic cells by induction of double-strand breaks in DNA. Inactivation of clbA and clbP in E. coli A192PP, a virulent strain of serotype O18:K1 that colonizes the gastrointestinal tract and translocates to the blood compartment with very high frequency in experimental infection of the neonatal rat, significantly reduced the capacity of A192PP to colonize the gut, engender double-strand breaks in DNA, and cause invasive, lethal disease. Mutation of clbA, which encodes a pleiotropic enzyme also involved in siderophore synthesis, impacted virulence to a greater extent than mutation of clbP, encoding an enzyme specific to colibactin synthesis. Restoration of colibactin gene function by complementation reestablished the fully virulent phenotype. We conclude that colibactin contributes to the capacity of E. coli K1 to colonize the neonatal gastrointestinal tract and to cause invasive disease in the susceptible neonate.E scherichia coli strains belonging to phylogenetic group B2 are found with increasing frequency in the feces of healthy individuals from high-income countries (1) and are responsible for a range of extraintestinal diseases that include urinary tract infections, sepsis, pneumonia, and neonatal meningitis (2). These extraintestinal pathogenic E. coli (ExPEC) strains carry genes encoding a diverse range of virulence determinants that promote colonization, invasion, survival in the blood compartment, and the capacity to evade host defenses and damage the host (3). These virulence-enhancing genes tend to cluster on pathogenicity islands, genomic elements that facilitate dissemination by horizontal gene transfer (4). The pks genomic island is found in 30% to 40% of E. coli B2 strains and codes for the production of colibactin, a polyketide-peptide genotoxin of as-yet-unknown chemical structure that causes doublestrand (ds) breaks in DNA, leading to cell cycle arrest, chromosome instability, and increased lymphopenia in septic rodents (5-8). Carriage of the pks island is linked to long-term persistence in the gastrointestinal (GI) tract (9), and pks-bearing strains represent a high-virulence subset within the B2 group (6). The 54-kb pks island encodes nonribosomal peptide synthases, polyketide synthases, and hybrid synthases, in addition to accessory, tailoring, and editing enzymes; the clbA gene encodes a phosphopantetheinyl transferase required for colibactin synthesis, and clbP specifies a D-amino peptidase involved in colibactin maturation (10, 11). The pks island also contributes to the synthesis of siderophore...

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The Genotoxin Colibactin Is a Determinant of Virulence in Escherichia coli K1 Experimental Neonatal Systemic Infection

et al. 2015

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“…Similar NRPS have been shown to be involved in the biosynthesis of piperazines or terphenylquinones from fungi (48,49). The largest gene cluster (cluster 4) encodes an NRPS-PKS hybrid with all structural features of the prodrug activation mechanism previously identified in the biosynthesis of xenocoumacin, zwittermicin, and colibactin (39,(50)(51)(52). Additionally, a putatively incomplete NRPS-PKS hybrid gene cluster (cluster 5 in Fig.…”

Section: Artificial Rearingmentioning

confidence: 83%

“…The m/z ratios observed in the different extracts are clearly in the range one would expect for the products of the identified gene clusters. Especially interesting is the hybrid PKS-NRPS gene cluster 4, encoding a compound that is most likely activated via proteolytic cleavage, as was shown for the potent antibiotic xenocoumacin from the entomopathogenic bacterium Xenorhabdus nematophila (39) and the still-unknown compound colibactin, a potent virulence factor of pathogenic Escherichia coli strains (51).…”

Section: Discussionmentioning

confidence: 99%

Low-Molecular-Weight Metabolites Secreted by Paenibacillus larvae as Potential Virulence Factors of American Foulbrood

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Fuchs

Bode

et al. 2014

Appl Environ Microbiol

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The spore-forming bacterium Paenibacillus larvae causes a severe and highly infective bee disease, American foulbrood (AFB). Despite the large economic losses induced by AFB, the virulence factors produced by P. larvae are as yet unknown. To identify such virulence factors, we experimentally infected young, susceptible larvae of the honeybee, Apis mellifera carnica, with different P. larvae isolates. Honeybee larvae were reared in vitro in 24-well plates in the laboratory after isolation from the brood comb. We identified genotype-specific differences in the etiopathology of AFB between the tested isolates of P. larvae, which were revealed by differences in the median lethal times. Furthermore, we confirmed that extracts of P. larvae cultures contain low-molecular-weight compounds, which are toxic to honeybee larvae. Our data indicate that P. larvae secretes metabolites into the medium with a potent honeybee toxic activity pointing to a novel pathogenic factor(s) of P. larvae. Genome mining of P. larvae subsp. larvae BRL-230010 led to the identification of several biosynthesis gene clusters putatively involved in natural product biosynthesis, highlighting the potential of P. larvae to produce such compounds.

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“…However, our laboratory has clearly shown the role of ClbP peptidase in colibactin maturation and activation. 27,28 Structural studies of this periplasmic protein revealed an active serine site, which is accessible to inhibitors and makes ClbP a potential target. 27,28 We therefore aimed at identifying small molecules able to bind and block the catalytic pocket of ClbP.…”

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“…27,28 Structural studies of this periplasmic protein revealed an active serine site, which is accessible to inhibitors and makes ClbP a potential target. 27,28 We therefore aimed at identifying small molecules able to bind and block the catalytic pocket of ClbP. 29 First, in silico docking experiments identified 2 boron-based compounds with computed ligand efficiency values consistent with results expected for medicinal chemistry leads.…”

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Targeting colorectal cancer-associated bacteria: A new area of research for personalized treatments

et al. 2016

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Most cases of colorectal cancer (CRC) are sporadic, and numerous studies have suggested that gut microbiota may play a crucial role in CRC development. Escherichia coli is a member of the gut microbiota frequently associated with colorectal tumors. CRC-associated E. coli strains frequently harbor the pks genomic island. This genomic island is responsible for the synthesis of colibactin genotoxin, which increases tumor numbers in CRC mouse models. We recently showed that targeting ClbP, a key enzyme involved in colibactin synthesis, blocks the deleterious effect of this toxin in vitro and leads to a significant decrease in tumor numbers in vivo. Altogether, our results suggest that the personalized treatment of CRC should also take into consideration the bacteria associated with the tumor in order to limit their deleterious effects.

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ClbP Is a Prototype of a Peptidase Subgroup Involved in Biosynthesis of Nonribosomal Peptides

Cited by 97 publications

References 40 publications

The Genotoxin Colibactin Is a Determinant of Virulence in Escherichia coli K1 Experimental Neonatal Systemic Infection

The Genotoxin Colibactin Is a Determinant of Virulence in Escherichia coli K1 Experimental Neonatal Systemic Infection

Low-Molecular-Weight Metabolites Secreted by Paenibacillus larvae as Potential Virulence Factors of American Foulbrood

Targeting colorectal cancer-associated bacteria: A new area of research for personalized treatments

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