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lipopolysaccharide modification in gram-negative bacteria during chronic infection.the gram-negative bacterial lipopolysaccharide (lps) is a major component of the outer membrane that plays a key role in host-pathogen interactions with the innate immune system. during infection, bacteria are exposed to a host environment that is typically dominated by inflammatory cells and soluble factors, including antibiotics, which provide cues about regulation of gene expression. bacterial adaptive changes including modulation of lps synthesis and structure are a conserved theme in infect ...201627075488
in vitro volatile organic compound profiling using gc×gc-tofms to differentiate bacteria associated with lung infections: a proof-of-concept study.chronic pulmonary infections are the principal cause of morbidity and mortality in individuals with cystic fibrosis (cf). due to the polymicrobial nature of these infections, the identification of the particular bacterial species responsible is an essential step in diagnosis and treatment. current diagnostic procedures are time-consuming, and can also be expensive, invasive and unpleasant in the absence of spontaneously expectorated sputum. the development of a rapid, non-invasive methodology ca ...201627120170
draft genome sequence of burkholderia cenocepacia strain ceib s5-2, a methyl parathion- and p-nitrophenol-degrading bacterium, isolated from agricultural soils in morelos, mexico.burkholderia cenocepacia is an opportunistic pathogen that belongs to burkholderia cepacia complex (bcc). burkholderia cenocepacia strain ceib s5-2 was isolated from agricultural soils in morelos, mexico, and previously has shown its abilities for bioremediation. in this study, we report the draft genome sequence of burkholderia cenocepacia strain ceib s5-2.201627125479
a burkholderia type vi effector deamidates rho gtpases to activate the pyrin inflammasome and trigger inflammation.burkholderia cenocepacia is an opportunistic pathogen of the cystic fibrosis lung that elicits a strong inflammatory response. b. cenocepacia employs a type vi secretion system (t6ss) to survive in macrophages by disarming rho-type gtpases, causing actin cytoskeletal defects. here, we identified teca, a non-vgrg t6ss effector responsible for actin disruption. teca and other bacterial homologs bear a cysteine protease-like catalytic triad, which inactivates rho gtpases by deamidating a conserved ...201627133449
structural features essential to the antimicrobial functions of human splunc1.splunc1 is an abundantly secreted innate immune protein in the mammalian respiratory tract that exerts bacteriostatic and antibiofilm effects, binds to lipopolysaccharide (lps), and acts as a fluid-spreading surfactant. here, we unravel the structural elements essential for the surfactant and antimicrobial functions of human splunc1 (short palate lung nasal epithelial clone 1). a unique α-helix (α4) that extends from the body of splunc1 is required for the bacteriostatic, surfactant, and lps bin ...201627145151
eradication and phenotypic tolerance of burkholderia cenocepacia biofilms exposed to atmospheric pressure non-thermal plasma.chronic lung infection with bacteria from the burkholderia cepacia complex (bcc), and in particular b. cenocepacia, is associated with significant morbidity and mortality in patients with cystic fibrosis (cf). b. cenocepacia can spread from person to person and exhibits intrinsic broad-spectrum antibiotic resistance. recently, atmospheric pressure non-thermal plasmas (apntps) have gained increasing attention as a novel approach to the prevention and treatment of a variety of hospital-acquired in ...201627179816
the crystal structure of burkholderia cenocepacia dfsa provides insights into substrate recognition and quorum sensing fatty acid biosynthesis.burkholderia cenocepacia is a major concern among respiratory tract infections in cystic fibrosis patients. this pathogen is particularly difficult to treat because of its high level of resistance to the clinically relevant antimicrobial agents. in b. cenocepacia, the quorum sensing cell-cell communication system is involved in different processes that are important for bacterial virulence, such as biofilm formation and protease and siderophore production. targeting the enzymes involved in this ...201627198181
a functional orit in the ptw plasmid of burkholderia cenocepacia can be recognized by the r388 relaxase trwc.burkholderia cenocepacia is both a plant pathogen and the cause of serious opportunistic infections, particularly in cystic fibrosis patients. b. cenocepacia k56-2 harbors a native plasmid named ptw for its involvement in the plant tissue watersoaking phenotype. ptw has also been reported to be important for survival in human cells. interestingly, the presence of ptwc, a homolog of the conjugative relaxase trwc of plasmid r388, suggests a possible function for ptw in conjugative dna transfer. th ...201627200362
the effect of mutation in the clpx gene on the synthesis of n-acyl-homoserine lactones and other properties of burkholderia cenocepacia 370.in order to study the regulation of n-acyl-homoserine lactones synthesis (ahls, the signal molecules of quorum sensing regulation) in burkholderia cenocepacia strain 370 we obtained mutants with increased ahl production. one of the mutants, named bc-b6, was obtained by tnmod-rkm(r) plasposon mutagenesis. the plasposon insertion was located within the clpx gene encoding the atpase subunit clpx of the clpxp protease. the mutation reduced bacterial virulence in mice intranasal infection. the result ...201727242147
cyanide toxicity to burkholderia cenocepacia is modulated by polymicrobial communities and environmental factors.microbes within polymicrobial communities can establish positive and negative interactions that have the potential to influence the overall behavior of the community. pseudomonas aeruginosa and species of the burkholderia cepacia complex (bcc) can co-exist in the lower airways, however several studies have shown that p. aeruginosa can effectively kill the bcc in vitro, for which hydrogen cyanide (hcn) was recently proposed to play a critical role. here we show that modification of the environmen ...201627242743
the burkholderia cenocepacia ompa-like protein bcal2958: identification, characterization, and detection of anti-bcal2958 antibodies in serum from b. cepacia complex-infected cystic fibrosis patients.respiratory infections by bacteria of the burkholderia cepacia complex (bcc) remain an important cause of morbidity and mortality among cystic fibrosis patients, highlighting the need for novel therapeutic strategies. in the present work we have studied the b. cenocepacia protein bcal2958, a member of the ompa-like family of proteins, demonstrated as highly immunogenic in other pathogens and capable of eliciting strong host immune responses. the encoding gene was cloned and the protein, produced ...201627325348
synthetic cystic fibrosis sputum medium regulates flagellar biosynthesis through the flhf gene in burkholderia cenocepacia.burkholderia cenocepacia belongs to the burkholderia cepacia complex (bcc), a group of at least 18 distinct species that establish chronic infections in the lung of people with the genetic disease cystic fibrosis (cf). the sputum of cf patients is rich in amino acids and was previously shown to increase flagellar gene expression in b. cenocepacia. we examined flagellin expression and flagellar morphology of b. cenocepacia grown in synthetic cystic fibrosis sputum medium (scfm) compared to minima ...201627379216
orderly replication and segregation of the four replicons of burkholderia cenocepacia j2315.bacterial genomes typically consist of a single chromosome and, optionally, one or more plasmids. but whole-genome sequencing reveals about ten per-cent of them to be multipartite, with additional replicons which by size and indispensability are considered secondary chromosomes. this raises the questions of how their replication and partition is managed without compromising genome stability and of how such genomes arose. vibrio cholerae, with a 1 mb replicon in addition to its 3 mb chromosome, i ...201627428258
the role of reactive oxygen species in antibiotic-induced cell death in burkholderia cepacia complex bacteria.it was recently proposed that bactericidal antibiotics, besides through specific drug-target interactions, kill bacteria by a common mechanism involving the production of reactive oxygen species (ros). however, this mechanism involving the production of hydroxyl radicals has become the subject of a lot of debate. since the contribution of ros to antibiotic mediated killing most likely depends on the conditions, differences in experimental procedures are expected to be at the basis of the conflic ...201627438061
elevated mirc1/mir17-92 cluster expression negatively regulates autophagy and cftr (cystic fibrosis transmembrane conductance regulator) function in cf macrophages.cystic fibrosis (cf) is a fatal, genetic disorder that critically affects the lungs and is directly caused by mutations in the cf transmembrane conductance regulator (cftr) gene, resulting in defective cftr function. macroautophagy/autophagy is a highly regulated biological process that provides energy during periods of stress and starvation. autophagy clears pathogens and dysfunctional protein aggregates within macrophages. however, this process is impaired in cf patients and cf mice, as their ...201627541364
discovery of new diketopiperazines inhibiting burkholderia cenocepacia quorum sensing in vitro and in vivo.burkholderia cenocepacia, an opportunistic respiratory pathogen particularly relevant for cystic fibrosis patients, is difficult to eradicate due to its high level of resistance to most clinically relevant antimicrobials. consequently, the discovery of new antimicrobials as well as molecules capable of inhibiting its virulence is mandatory. in this regard quorum sensing (qs) represents a good target for anti-virulence therapies, as it has been linked to biofilm formation and is important for the ...201627580679
a novel method for investigating burkholderia cenocepacia infections in patients with cystic fibrosis and other chronic diseases of the airways.burkholderia cenocepacia is a gram-negative, opportunistic pathogen that is a cause of morbidity and mortality in patients with cystic fibrosis (cf). research efforts over the past few decades contributed to our understanding of these infections by identifying virulence factors. however, little is known about how this pathogen adapts to the harsh environment found inside the cf airways, which is characterized by a unique mucus containing high concentrations of inflammatory markers. the current s ...201627586172
candidate essential genes in burkholderia cenocepacia j2315 identified by genome-wide tradis.burkholderia cenocepacia infection often leads to fatal cepacia syndrome in cystic fibrosis patients. however, antibiotic therapy rarely results in complete eradication of the pathogen due to its intrinsic resistance to many clinically available antibiotics. recent attention has turned to the identification of essential genes as the proteins encoded by these genes may serve as potential targets for development of novel antimicrobials. in this study, we utilized tradis (transposon directed insert ...201627597847
structural differences in gut bacteria communities in developmental stages of natural populations of lutzomyia evansi from colombia's caribbean coast.lutzomyia evansi, a phlebotomine insect endemic to colombia's caribbean coast, is considered to be the main vector of visceral and cutaneous leishmaniasis in the region. although insects of this species can harbor pathogenic and non-pathogenic microorganisms in their intestinal microbiota, there is little information available about the diversity of gut bacteria present in lutzomyia evansi. in this study, conventional microbiological methods and molecular tools were used to assess the compositio ...201627618991
antibiotic resistance in burkholderia species.the genus burkholderia comprises metabolically diverse and adaptable gram-negative bacteria, which thrive in often adversarial environments. a few members of the genus are prominent opportunistic pathogens. these include burkholderia mallei and burkholderia pseudomallei of the b. pseudomallei complex, which cause glanders and melioidosis, respectively. burkholderia cenocepacia, burkholderia multivorans, and burkholderia vietnamiensis belong to the burkholderia cepacia complex and affect mostly c ...201627620956
variation of burkholderia cenocepacia virulence potential during cystic fibrosis chronic lung infection.during long-term lung infection in cystic fibrosis (cf) patients, burkholderia cenocepacia faces multiple selective pressures in this highly stressful and fluctuating environment. as a consequence, the initial infecting strain undergoes genetic changes that result in the diversification of genotypes and phenotypes. whether this clonal expansion influences the pathogenic potential is unclear. the virulence potential of 39 sequential b. cenocepacia (reca lineage iiia) isolates, corresponding to 3 ...201627652671
combination antimicrobial susceptibility testing of burkholderia cepacia complex: significance of species.the burkholderia cepacia complex (bcc) is notorious for the life-threatening pulmonary infections it causes in patients with cystic fibrosis. the multidrug-resistant nature of bcc and differing infective bcc species make the design of appropriate treatment regimens challenging. previous synergy studies have failed to take account of the species of bcc isolates. etest methodology was used to facilitate minimum inhibitory concentration (mic) and antimicrobial combination testing on 258 isolates of ...201627665523
the fitness effects of spontaneous mutations nearly unseen by selection in a bacterium with multiple chromosomes.mutation accumulation (ma) experiments employ the strategy of minimizing the population size of evolving lineages to greatly reduce effects of selection on newly arising mutations. thus, most mutations fix within ma lines independently of their fitness effects. this approach, more recently combined with genome sequencing, has detailed the rates, spectra, and biases of different mutational processes. however, a quantitative understanding of the fitness effects of mutations virtually unseen by sel ...201627672096
burkholderia cenocepacia k56-2 trimeric autotransporter adhesin bcaa binds tnfr1 and contributes to induce airway inflammation.chronic lung disease caused by persistent bacterial infections is a major cause of morbidity and mortality in patients with cystic fibrosis (cf). cf pathogens acquire antibiotic resistance, overcome host defenses, and impose uncontrolled inflammation that ultimately may cause permanent damage of lungs' airways. among the multiple cf-associated pathogens, burkholderia cenocepacia and other burkholderia cepacia complex bacteria have become prominent contributors of disease progression. here, we de ...201727684048
the temperate burkholderia phage ap3 of the peduovirinae shows efficient antimicrobial activity against b. cenocepacia of the iiia lineage.burkholderia phage ap3 (vb_bcem_ap3) is a temperate virus of the myoviridae and the peduovirinae subfamily (p2likevirus genus). this phage specifically infects multidrug-resistant clinical burkholderia cenocepacia lineage iiia strains commonly isolated from cystic fibrosis patients. ap3 exhibits high pairwise nucleotide identity (61.7 %) to burkholderia phage ks5, specific to the same b. cenocepacia host, and has 46.7-49.5 % identity to phages infecting other species of burkholderia. the lysis c ...201727770178
burkholderia cenocepacia virulence microevolution in the cf lung: variations on a theme. 201627786605
competitive growth enhances conditional growth mutant sensitivity to antibiotics and exposes a two-component system as an emerging antibacterial target in burkholderia cenocepacia.chemogenetic approaches to profile an antibiotic mode of action are based on detecting differential sensitivities of engineered bacterial strains in which the antibacterial target (usually encoded by an essential gene) or an associated process is regulated. we previously developed an essential-gene knockdown mutant library in the multidrug-resistant burkholderia cenocepacia by transposon delivery of a rhamnose-inducible promoter. in this work, we used illumina sequencing of multiplex-pcr-amplifi ...201727799222
an efficient system for the generation of marked genetic mutants in members of the genus burkholderia.to elucidate the function of a gene in bacteria it is vital that targeted gene inactivation (allelic replacement) can be achieved. allelic replacement is often carried out by disruption of the gene of interest by insertion of an antibiotic-resistance marker followed by subsequent transfer of the mutant allele to the genome of the host organism in place of the wild-type gene. however, due to their intrinsic resistance to many antibiotics only selected antibiotic-resistance markers can be used in ...201727825973
crystal structure of bacterial haem importer complex in the inward-facing conformation.pathogenic bacteria remove iron from the haem of host tissues and use it as a catalytic center of many enzymes. haem uptake by pathogenic bacteria is facilitated by the membrane-integrated haem importer, which belongs to the type ii atp-binding cassette (abc) transporter. here we present crystal structures of burkholderia cenocepacia haem importer bhuuv complexed with the periplasmic haem-binding protein bhut and in the absence of bhut. the transmembrane helices of these structures show an inwar ...201627830695
bacterial proteases and haemostasis dysregulation in the cf lung.pathogenic bacteria which chronically colonise the cystic fibrosis (cf) lung produce a number of virulence determinants, including distinct proteolytic activities. the potential role bacterial proteases play on haemostatic dysregulation within the cf lung is, however, poorly defined, despite haemoptysis being a common complication in cf.201727839953
tri- and tetravalent mannoclusters cross-link and aggregate bc2l-a lectin from burkholderia cenocepacia.the opportunistic gram-negative bacterium burkholderia cenocepacia causes lethal infections in cystic fibrosis patients. multivalent mannoside derivatives were prepared as potential inhibitors of lectin bc2l-a, one of the virulence factors deployed by b. cenocepacia in the infection process. an (α1→2)-thio-linked mannobioside mimic bearing an azide functionalized aglycon was conjugated to different multivalent scaffolds such as propargylated calix[4]arenes, methyl gallate and pentaerythritol by ...201727871013
the burkholderia cenocepacia peptidoglycan-associated lipoprotein is involved in epithelial cell attachment and elicitation of inflammation.the burkholderia cepacia complex (bcc) is a group of gram-negative opportunistic pathogens causing infections in people with cystic fibrosis (cf). bcc is highly antibiotic resistant, making conventional antibiotic treatment problematic. the identification of novel targets for anti-virulence therapies should improve therapeutic options for infected cf patients. we previously identified that the peptidoglycan-associated lipoprotein (pal) was immunogenic in bcc infected cf patients; however, its ro ...201727886433
biochemical characterization of glutamate racemase-a new candidate drug target against burkholderia cenocepacia infections.the greatest obstacle for the treatment of cystic fibrosis patients infected with the burkholderia species is their intrinsic antibiotic resistance. for this reason, there is a need to develop new effective compounds. glutamate racemase, an essential enzyme for the biosynthesis of the bacterial cell wall, is an excellent candidate target for the design of new antibacterial drugs. to this aim, we recombinantly produced and characterized glutamate racemase from burkholderia cenocepacia j2315. from ...201627898711
mouse intestinal niche cells express a distinct α1,2-fucosylated glycan recognized by a lectin from burkholderia cenocepacia.in this study, we examined the distribution of fucosylated glycans in mouse intestines using a lectin, bc2lcn (n-terminal domain of the lectin bc2l-c from burkholderia cenocepacia), as a probe. bc2lcn is specific for glycans with a terminal fucα1,2galβ1,3-motif and it is a useful marker for discriminating the undifferentiated status of human induced/embryonic stem cells. apparent bc2lcn reactivity was detected in the secretory granules of goblet cells in the ileum but not those in the colon. we ...201627979999
using dendritic cells to evaluate how burkholderia cenocepacia clonal isolates from a chronically infected cystic fibrosis patient subvert immune functions.infection with burkholderia cepacia complex (bcc) bacteria is a threat to cystic fibrosis (cf) patients, commonly leading to a fatal pneumonia, the cepacia syndrome. it causes a massive production of pro-inflammatory cytokines and leucocyte recruitment to airway epithelium without resolving infection and contributing to tissue lesion. to dissect how bcc bacteria subvert the immune response, we developed a co-culture model with human dendritic cells (dcs) and b. cenocepacia clonal variants isolat ...201727987042
cheating fosters species co-existence in well-mixed bacterial communities.explaining the enormous biodiversity observed in bacterial communities is challenging because ecological theory predicts that competition between species occupying the same niche should lead to the exclusion of less competitive community members. competitive exclusion should be particularly strong when species compete for a single limiting resource or live in unstructured habitats that offer no refuge for weaker competitors. here, we describe the 'cheating effect', a form of intra-specific compe ...201728060362
(1)h-nmr-based endometabolome profiles of burkholderia cenocepacia clonal variants retrieved from a cystic fibrosis patient during chronic infection.during cystic fibrosis (cf) chronic lung infections, bacteria of the burkholderia cepacia complex (bcc) are exposed for several years to a stressful and changing environment. these environmental challenges results in genetic changes of the initial infecting strain with the consequent diversification of genotypes and phenotypes. the exploitation of functional and comparative genomic approaches has suggested that such diversification is associated with massive metabolic remodeling but these altera ...201628066350
the lpxl acyltransferase is required for normal growth and penta-acylation of lipid a in burkholderia cenocepacia.lipid a anchors the lipopolysaccharide (lps) to the outer membrane and is usually composed of a hexa-acylated diglucosamine backbone. burkholderia cenocepacia, an opportunistic pathogen, produces a mixture of tetra- and penta-acylated lipid a. "late" acyltransferases add secondary acyl chains to lipid a after the incorporation of four primary acyl chains to the diglucosamine backbone. here, we report that b. cenocepacia has only one late acyltransferase, lpxl (bcal0508), which adds a myristoyl c ...201728085228
human cystic fibrosis macrophages have defective calcium-dependent protein kinase c activation of the nadph oxidase, an effect augmented by burkholderia cenocepacia.macrophage intracellular pathogen killing is defective in cystic fibrosis (cf), despite abundant production of reactive oxygen species (ros) in lung tissue. burkholderia species can cause serious infection in cf and themselves affect key oxidase components in murine non-cf cells. however, it is unknown whether human cf macrophages have an independent defect in the oxidative burst and whether burkholderia contributes to this defect in terms of assembly of the nadph oxidase complex and subsequent ...201728093527
mouse intestinal niche cells express a distinct α1,2-fucosylated glycan recognized by a lectin from burkholderia cenocepacia. 201728177462
biocontrol of burkholderia cepacia complex bacteria and bacterial phytopathogens by bdellovibrio bacteriovorus.bdellovibrio and like organisms are predatory bacteria that have the unusual property of using the cytoplasmic constituents of other gram-negative bacteria as nutrients. these predators may thus provide an alternative approach to the biocontrol of human and plant pathogens. predators were isolated on burkholderia cenocepacia k56-2 and j2315 as prey cells, in enrichment cultures with soil and sewage. three isolates (dm7c, dm8a, and dm11a) were identified as bdellovibrio bacteriovorus on the basis ...201728177793
synthetic cystic fibrosis sputum medium diminishes <i>burkholderia cenocepacia</i> antifungal activity against <i>aspergillus fumigatus</i> independently of phenylacetic acid production.phenylacetic acid (paa), an intermediate of phenylalanine degradation, is emerging as a signal molecule in microbial interactions with the host. in this work, we explore the presence of phenylalanine and paa catabolism in three microbial pathogens of the cystic fibrosis (cf) lung microbiome: <i>pseudomonas aeruginosa</i>, <i>burkholderia cenocepacia</i> and <i>aspergillus fumigatus</i>. while <i>in silico</i> analysis of <i>b. cenocepacia</i> j2315 and <i>a. fumigatus</i> af293 genome sequences ...201728178425
evaluation of combination therapy for burkholderia cenocepacia lung infection in different in vitro and in vivo models.burkholderia cenocepacia is an opportunistic pathogen responsible for life-threatening infections in cystic fibrosis patients. b. cenocepacia is extremely resistant towards antibiotics and therapy is complicated by its ability to form biofilms. we investigated the efficacy of an alternative antimicrobial strategy for b. cenocepacia lung infections using in vitro and in vivo models. a screening of the nih clinical collection 1&2 was performed against b. cenocepacia biofilms formed in 96-well micr ...201728248999
a broad host range tailocin from burkholderia cenocepacia.the burkholderia cepacia complex (bcc) consists of 20 closely related gram-negative bacterial species that are significant pathogens for persons with cystic fibrosis (cf). some bcc strains are highly transmissible and resistant to multiple antibiotics, making infection difficult to treat. a tailocin (phage-tail-like bacteriocin), designated bcetmilo, with broad host range against members of the bcc was identified in burkholderia cenocepacia strain bc0425. sixty-eight percent of bcc representing ...201728258146
antibiotic capture by bacterial lipocalins uncovers an extracellular mechanism of intrinsic antibiotic resistance.the potential for microbes to overcome antibiotics of different classes before they reach bacterial cells is largely unexplored. here we show that a soluble bacterial lipocalin produced by burkholderia cenocepacia upon exposure to sublethal antibiotic concentrations increases resistance to diverse antibiotics in vitro and in vivo these phenotypes were recapitulated by heterologous expression in b. cenocepacia of lipocalin genes from pseudomonas aeruginosa, mycobacterium tuberculosis, and methici ...201728292982
sequential burkholderia cenocepacia isolates from siblings with cystic fibrosis show increased lung cell attachment. 201728294652
peptide modification results in the formation of a dimer with a 60-fold enhanced antimicrobial activity.cationic antimicrobial peptides (camps) occur naturally in numerous organisms and are considered as a class of antibiotics with promising potential against multi-resistant bacteria. herein, we report a strategy that can lead to the discovery of novel small camps with greatly enhanced antimicrobial activity and retained antibiofilm potential. we geared our efforts towards i) the n-terminal cysteine functionalization of a previously reported small synthetic cationic peptide (peptide 1037, krfrirvr ...201728296935
phenotypic diversity and genotypic flexibility of burkholderia cenocepacia during long-term chronic infection of cystic fibrosis lungs.chronic bacterial infections of the lung are the leading cause of morbidity and mortality in cystic fibrosis patients. tracking bacterial evolution during chronic infections can provide insights into how host selection pressures-including immune responses and therapeutic interventions-shape bacterial genomes. we carried out genomic and phenotypic analyses of 215 serially collected burkholderia cenocepacia isolates from 16 cystic fibrosis patients, spanning a period of 2-20 yr and a broad range o ...201728325850
identification and analysis of genomic islands in burkholderia cenocepacia au 1054 with emphasis on pathogenicity islands.genomic islands (gis) are genomic regions that reveal evidence of horizontal dna transfer. they can code for many functions and may augment a bacterium's adaptation to its host or environment. gis have been identified in strain j2315 of burkholderia cenocepacia, whereas in strain au 1054 there has been no published works on such regions according to our text mining and keyword search in medline.201728347342
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