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bacillus anthracis o-succinylbenzoyl-coa synthetase: reaction kinetics and a novel inhibitor mimicking its reaction intermediate.o-succinylbenzoyl-coa (osb-coa) synthetase (ec 6.2.1.26) catalyzes the atp-dependent condensation of o-succinylbenzoate (osb) and coa to form osb-coa, the fourth step of the menaquinone biosynthetic pathway in bacillus anthracis. gene knockout studies have highlighted this enzyme as a potential target for the discovery of new antibiotics. here we report the first studies on the kinetic mechanism of b. anthracis osb-coa synthetase, classifying it as an ordered bi uni uni bi ping-pong mechanism. t ...200818973344
germline humanization of a non-human primate antibody that neutralizes the anthrax toxin, by in vitro and in silico engineering.fab 35pa83 is an antibody fragment of non-human primate origin that neutralizes the anthrax lethal toxin. human antibodies are usually preferred when clinical use is envisioned, even though their framework regions (fr) may carry mutations introduced during affinity maturation. these hypermutations can be immunogenic and therefore fr that are encoded by human germline genes, encountered in igms and thus part of the "self" proteins, are preferable. accordingly, the proportion of fr residues in 35p ...200818976662
bacillus anthracis peptidoglycan stimulates an inflammatory response in monocytes through the p38 mitogen-activated protein kinase pathway.we hypothesized that the peptidoglycan component of b. anthracis may play a critical role in morbidity and mortality associated with inhalation anthrax. to explore this issue, we purified the peptidoglycan component of the bacterial cell wall and studied the response of human peripheral blood cells. the purified b. anthracis peptidoglycan was free of non-covalently bound protein but contained a complex set of amino acids probably arising from the stem peptide. the peptidoglycan contained a polys ...200819002259
[the anthrax researcher took his life--was he a bioterrorist?]. 200819006871
risk factors associated with anthrax outbreak in animals in north dakota, 2005: a retrospective case-control study.we identified the risk factors associated with the anthrax outbreak of 2005 in animals in north dakota.200819006977
synthetic and crystallographic studies of a new inhibitor series targeting bacillus anthracis dihydrofolate reductase.bacillus anthracis, the causative agent of anthrax, poses a significant biodefense danger. serious limitations in approved therapeutics and the generation of resistance have produced a compelling need for new therapeutic agents against this organism. bacillus anthracis is known to be insensitive to the clinically used antifolate, trimethoprim, because of a lack of potency against the dihydrofolate reductase enzyme. herein, we describe a novel lead series of b. anthracis dihydrofolate reductase i ...200819007108
development of isothermal taqman assays for detection of biothreat organisms.taqman probe (dual-labeled dna probe)-based real-time detection, one of the most sensitive and specific fluorescent detection methods, has been widely utilized in conjunction with polymerase chain reaction (pcr). helicase-dependent amplification (hda) is an isothermal amplification technology that has a similar reaction scheme to pcr, but replaces thermocycling with a helicase capable of unwinding a dna duplex. here we describe a novel isothermal real-time detection method (hda-taqman) that comb ...200819007339
responding to a bioterrorism attack-one scenario: part 2.this article continues the discussions introduced in the earlier article submitted to the health care manager that is titled epidemic simulation for syndromic surveillance, where a format for analysis of the incidence of a bioterrorist attack was presented. part 2 of this series provides a discussion of the observed outcomes from the simulation techniques. this simulation was conducted as part of a federal grant award administered through the center for biological defense at the university of so ...200819011411
transcriptional and apoptotic responses of thp-1 cells to challenge with toxigenic, and non-toxigenic bacillus anthracis.bacillus anthracis secretes several virulence factors targeting different host organs and cell types during inhalational anthrax infection. the bacterial expression of a key virulence factor, lethal toxin (letx) is closely tied to another factor, edema toxin (edtx). both are transcribed on the same virulence plasmid (pxo1) and both have been the subject of much individual study. their combined effect during virulent anthrax likely modulates both the global transcriptional and the phenotypic resp ...200819014542
evidence-based spectrum of antimicrobial activity for disinfection of bronchoscopes.processing of bronchoscopes after a physical examination has to eliminate all micro-organisms that could have contaminated the endoscope and that may harm the following patient. the aim of this analysis is to define those micro-organisms that may contaminate the bronchoscope during the examination and that may cause disease in other patients.200818994685
novel acyl phosphate mimics that target plsy, an essential acyltransferase in gram-positive bacteria.plsy is a recently discovered acyltransferase that executes an essential step in membrane phospholipid biosynthesis in gram- positive bacteria. by using a bioisosteric replacement approach to generate substrate-based inhibitors of plsy as potential novel antibacterial agents, a series of stabilized acyl phosphate mimetics, including acyl phosphonates, acyl alpha,alpha-difluoromethyl phosphonates, acyl phosphoramides, reverse amide phosphonates, acyl sulfamates, and acyl sulfamides were designed ...200819016283
identification, characterization and activation mechanism of a tyrosine kinase of bacillus anthracis.bacillus subtilis has three active tyrosine kinases, ptka, ptkb and mcsb, which play an important role in the physiology of the bacterium. genome sequence analysis and biochemical experiments indicated that the ortholog of mcsb, bas0080, is the only active tyrosine kinase present in bacillus anthracis. the autophosphorylation of mcsb of b. anthracis was enhanced in the presence of an activator protein mcsa (bas0079), a property similar to that reported for b. subtilis. however, the process of en ...200819016839
medical toxicology and public health-update on research and activities at the centers for disease control and prevention and the agency for toxic substances and disease registry.an extensive review of cdc epidemiological responses to human outbreaks of anthrax from occupational settings between the years of 1950 and 2001 documented a variety of approaches to mitigation and decontamination [2]. these approaches included taking no action, burning contaminated materials, chlorinating water supplies, instituting administrative and engineering controls and ppe, vaccinating potentially exposed individuals, and in 2 instances, fumigating with formaldehyde vapor (now considered ...200819031383
spatial localization of bacteria controls coagulation of human blood by 'quorum acting'.blood coagulation often accompanies bacterial infections and sepsis and is generally accepted as a consequence of immune responses. though many bacterial species can directly activate individual coagulation factors, they have not been shown to directly initiate the coagulation cascade that precedes clot formation. here we demonstrated, using microfluidics and surface patterning, that the spatial localization of bacteria substantially affects coagulation of human and mouse blood and plasma. bacil ...200819031531
mastitis caused by bacillus anthracis in a beef cow.a mixed-breed beef cow was presented with swelling of the front and hind left quarters of the mammary gland and mild depression. direct examination and culture of the serosanguinous-like milk samples collected from these quarters were consistent with bacillus anthracis infection.200819043486
nanotube-assisted protein deactivation.conjugating proteins onto carbon nanotubes has numerous applications in biosensing, imaging and cellular delivery. however, remotely controlling the activity of proteins in these conjugates has never been demonstrated. here we show that upon near-infrared irradiation, carbon nanotubes mediate the selective deactivation of proteins in situ by photochemical effects. we designed nanotube-peptide conjugates to selectively destroy the anthrax toxin, and also optically transparent coatings that can se ...200818654449
characterization of bacillus anthracis iron-regulated surface determinant (isd) proteins containing neat domains.three iron-regulated surface determinant (isd) proteins, containing near transporter (neat) domains (gbaa4789-7), constitute part of an eight-member bacillus anthracis operon. gbaa4789 (isdc), previously characterized by others as a haem-binding protein, and two novel isd proteins characterized in this study, gbaa4788 (isdj) and gbaa4787 (isdk) proteins, can be translated from two alternative overlapping transcriptional units. the three neat-containing isd proteins are shown to be expressed in v ...200818826411
effects of a reduced dose schedule and intramuscular administration of anthrax vaccine adsorbed on immunogenicity and safety at 7 months: a randomized trial.in 1999, the us congress directed the centers for disease control and prevention to conduct a pivotal safety and efficacy study of anthrax vaccine adsorbed (ava).200818827210
aryl acid adenylating enzymes involved in siderophore biosynthesis: fluorescence polarization assay, ligand specificity, and discovery of non-nucleoside inhibitors via high-throughput screening.the design and synthesis of a fluorescent probe fl-sal-ams 6 based on the tight-binding inhibitor 5'- o-[ n-(salicyl)sulfamoyl]adenosine (sal-ams) is described for the aryl acid adenylating enzymes (aaaes) known as mbta, ybte, ente, vibe, dhbe, and base involved in siderophore biosynthesis from mycobacterium tuberculosis, yersinia pestis, escherichia coli, vibrio cholerae, bacillus subtilis, and acinetobacter baumannii, respectively. the probe was successfully used to develop a fluorescence pola ...200818928302
structure of nicotinic acid mononucleotide adenylyltransferase from bacillus anthracis.nicotinic acid mononucleotide adenylyltransferase (namnat; ec 2.7.7.18) is the penultimate enzyme in the biosynthesis of nad(+) and catalyzes the adenylation of nicotinic acid mononucleotide (namn) by atp to form nicotinic acid adenine dinucleotide (naad). this enzyme is regarded as a suitable candidate for antibacterial drug development; as such, bacillus anthracis namnat (ba namnat) was heterologously expressed in escherichia coli for the purpose of inhibitor discovery and crystallography. the ...200818931430
cell wall anchor structure of bcpa pili in bacillus anthracis.assembly of pili in gram-positive bacteria and their attachment to the cell wall envelope are mediated by sortases. in bacillus cereus and its close relative bacillus anthracis, the major pilin protein bcpa is cleaved between the threonine and the glycine of its c-terminal lpxtg motif sorting signal by the pilin-specific sortase d. the resulting acyl enzyme intermediate is relieved by the nucleophilic attack of the side-chain amino group of lysine within the ypkn motif of another bcpa subunit. c ...200818940793
association and decontamination of bacillus spores in a simulated drinking water system.the objective of this work was to elucidate the disinfectant susceptibility of bacillus anthracis sterne (ba) and a commercial preparation of bacillus thuringiensis (bt) spores associated with a simulated drinking water system. biofilms composed of indigenous water system bacteria were accumulated on copper and polyvinyl chloride (pvc) pipe material surfaces in a low-flow pipe loop and uniformly mixed tank reactor (cdc biofilm reactor). application of a distributed shear during spore contact res ...200818947853
using mahalanobis distance to compare genomic signatures between bacterial plasmids and chromosomes.plasmids are ubiquitous mobile elements that serve as a pool of many host beneficial traits such as antibiotic resistance in bacterial communities. to understand the importance of plasmids in horizontal gene transfer, we need to gain insight into the 'evolutionary history' of these plasmids, i.e. the range of hosts in which they have evolved. since extensive data support the proposal that foreign dna acquires the host's nucleotide composition during long-term residence, comparison of nucleotide ...200818953039
structural and functional analysis of asbf: origin of the stealth 3,4-dihydroxybenzoic acid subunit for petrobactin biosynthesis.petrobactin, a virulence-associated siderophore produced by bacillus anthracis, chelates ferric iron through the rare 3,4-isomer of dihydroxybenzoic acid (3,4-dhba). most catechol siderophores, including bacillibactin and enterobactin, use 2,3-dhba as a biosynthetic subunit. significantly, siderocalin, a factor involved in human innate immunity, sequesters ferric siderophores bearing the more typical 2,3-dhba moiety, thereby impeding uptake of iron by the pathogenic bacterial cell. in contrast, ...200818955706
anthrax edema toxin modulates pka- and creb-dependent signaling in two phases.anthrax edema toxin (edtx) is an adenylate cyclase which operates in the perinuclear region of host cells. however, the action of edtx is poorly understood, especially at molecular level. the ability of edtx to modulate camp-dependent signaling was studied in jurkat t cells and was compared with that of other camp-rising agents: bordetella pertussis adenylate cyclase toxin, cholera toxin and forskolin.200818958164
anthrax in transit; practical experience and intellectual exchange.focusing on three anglo-american outbreaks of industrial anthrax, this essay engages the question of how local circumstances influenced the transmission of scientific knowledge in the late nineteenth century. walpole (massachusetts), glasgow, and bradford (yorkshire) served as important nodes of transnational investigation into anthrax. knowledge about the morphology and behavior of bacillus anthracis changed little while in transit between these nodes, even during complex debates about the natu ...200818959192
functional peg-modified thin films for biological detection.we report a general procedure to prepare functional organic thin films for biological assays on oxide surfaces. silica surfaces were functionalized by self-assembly of an amine-terminated silane film using both vapor- and solution-phase deposition of 3'-aminopropylmethyldiethoxysilane (apmdes). we found that vapor-phase deposition of apmdes under reduced pressure produced the highest quality monolayer films with uniform surface coverage, as determined by atomic force microscopy (afm), ellipsomet ...200818229965
fieldable genotyping of bacillus anthracis and yersinia pestis based on 25-loci multi locus vntr analysis.anthrax and plague are diseases caused by bacillus anthracis and yersinia pestis respectively. these bacteria are etiological agents for worldwide zoonotic diseases and are considered among the most feared potential bioterror agents. strain differentiation is difficult for these microorganisms because of their high intraspecies genome homogeneity. moreover, fast strain identification and comparison with known genotypes may be crucial for naturally occurring outbreaks versus bioterrorist events d ...200818230125
waterborne pathogen detection using raman spectroscopy.raman spectroscopy is being evaluated as a candidate technology for waterborne pathogen detection. we have investigated the impact of key experimental and background interference parameters on the bacterial species level identification performance of raman detection. these parameters include laser-induced photodamage threshold, composition of water matrix, and organism aging in water. the laser-induced photodamage may be minimized by operating a 532 nm continuous wave laser excitation at laser p ...200818230198
synthesis of a hexasaccharide repeating unit from bacillus anthracis vegetative cell walls.the first synthesis of hexasaccharide 1 representing a repeat unit of a polysaccharide specific to the vegetative cell wall of bacillus anthracis is reported. the synthetic hexasaccharide is equipped with an n-pentenyl handle at the reducing terminus to allow for further functionalization. key transformations during the synthesis are the conversion of a glucose into a mannosazide residue, a (2+2) coupling, followed by double alpha-galactosylation to furnish the hexasaccharide, and global deprote ...200818232704
influence of nisin on the resistance of bacillus anthracis sterne spores to heat and hydrostatic pressure.the influence of nisin on the heat and pressure resistance of bacillus anthracis sterne spores was examined. the decimal reduction times (d-value) of spores in milk (2% fat) at 80, 85, and 90 degrees c were determined. in the absence of nisin, the d-values were 30.09, 9.30, and 3.86 min, respectively. the d-values of spores heated in the presence of nisin (1 mg/ml) were not significantly different (p = 0.05). however, spores heated in the presence of nisin had a 1- to 2-log reduction in viabilit ...200818236684
a high resolution four-locus multiplex single nucleotide repeat (snr) genotyping system in bacillus anthracis.the allelic identities of single nucleotide repeat (snr) markers in bacillus anthracis are typically ascertained by dna sequencing through the direct repeat. here we describe a reproducible method for genotyping closely related isolates by using four snr loci in a multiplex-pcr capillary electrophoresis system amenable to high-throughput analysis.200818237793
structure and specificity of lamprey monoclonal antibodies.adaptive immunity in jawless vertebrates (lamprey and hagfish) is mediated by lymphocytes that undergo combinatorial assembly of leucine-rich repeat (lrr) gene segments to create a diverse repertoire of variable lymphocyte receptor (vlr) genes. immunization with particulate antigens induces vlr-b-bearing lymphocytes to secrete antigen-specific vlr-b antibodies. here, we describe the production of recombinant vlr-b antibodies specific for bcla, a major coat protein of bacillus anthracis spores. t ...200818238899
deletion of dnan1 generates a mutator phenotype in bacillus anthracis.the dnan gene in eubacteria is an essential gene that encodes the beta subunit of replicative dna polymerase. nearly all eubacterial genomes sequenced to date predict a single copy of the dnan gene in a well-conserved neighboring gene context. however, 19 genomes out of 348 scanned, including bacillus anthracis, bacillus cereus, bacillus thuringiensis, and bacillus weihenstephanensis, predict more than one dnan gene. in most cases, these genomes appear to maintain a copy of the dnan homolog in i ...200818242150
performance evaluation of five commercial real-time pcr reagent systems using taqman assays for b. anthracis detection.real-time pcr assay sensitivity is affected by the choice and concentrations of reaction mix constituents among other factors such as primers, probes, and analytical assay platforms. commercially available reagent mixes facilitate pcr assay set-up with fewer steps and timeliness. however, determination of analytical assay framework is important for ready-to-use real-time pcr reagent systems for rapid, quantitative and accurate detection of bioterror pathogens such as bacillus anthracis.200818242168
binding of n-terminal fragments of anthrax edema factor (ef(n)) and lethal factor (lf(n)) to the protective antigen pore.anthrax toxin consists of three different molecules: the binding component protective antigen (pa, 83 kda), and the enzymatic components lethal factor (lf, 90 kda) and edema factor (ef, 89 kda). the 63 kda c-terminal part of pa, pa(63), forms heptameric channels that insert in endosomal membranes at low ph, necessary to translocate ef and lf into the cytosol of target cells. in many studies, about 30 kda n-terminal fragments of the enzymatic components ef (254 amino acids) and lf (268 amino acid ...200818243126
anthrose biosynthetic operon of bacillus anthracis.the exosporium of bacillus anthracis spores consists of a basal layer and an external hair-like nap. the nap is composed primarily of the glycoprotein bcla, which contains a collagen-like region with multiple copies of a pentasaccharide side chain. this oligosaccharide possesses an unusual terminal sugar called anthrose, followed by three rhamnose residues and a protein-bound n-acetylgalactosamine. based on the structure of anthrose, we proposed an enzymatic pathway for its biosynthesis. examina ...200818245286
potent inhibition of tumor angiogenesis by the matrix metalloproteinase-activated anthrax lethal toxin: implications for broad anti-tumor efficacy.angiogenesis is a critical step in solid tumor progression. the mitogen-activated protein kinase (mapk) signaling pathways are central to this process, and thus present attractive targets for angiogenesis inhibition. anthrax lethal toxin (letx), secreted from the gram positive bacillus anthracis, demonstrates potent mapk pathway inhibition. in vivo efficacy studies revealed that letx has broad anti-tumor efficacy via the targeting of angiogenesis. however, specificity in animal models was limite ...200818245947
antibody responses of variable lymphocyte receptors in the lamprey.lamprey and hagfish, the living representatives of jawless vertebrates, use genomic leucine-rich-repeat cassettes for the combinatorial assembly of diverse antigen receptor genes encoding variable lymphocyte receptors of two types: vlra and vlrb. we describe here the vlrb-bearing lineage of lymphocytes in sea lamprey. these cells responded to repetitive carbohydrate or protein determinants on bacteria or mammalian cells with lymphoblastoid transformation, proliferation and differentiation into p ...200818246071
analysis of epitope information related to bacillus anthracis and clostridium botulinum.we have reviewed the information about epitopes of immunological interest from clostridium botulinum and bacillus anthracis, by mining the immune epitope database and analysis resource. for both pathogens, the vast majority of epitopes reported to date are derived from a single protein: the protective antigen of b. anthracis and the neurotoxin type a of c. botulinum. a detailed analysis of the data was performed to characterize the function, localization and conservancy of epitopes identified as ...200818251694
detoxified lethal toxin as a potential mucosal vaccine against anthrax.the nontoxic mutant lethal factor (mlf; which has the e687c substitution) and functional protective antigen (pa63) of bacillus anthracis were evaluated for their use as mucosal vaccines against anthrax in a/j mice. intranasal vaccination of three doses of 30 microg of mlf or 60 microg of pa63 elicited significant serum and mucosal antibody responses, with anthrax lethal toxin-neutralizing titers of 40 and 60 in immune sera, respectively. however, only 30% and 60% of the vaccinated animals in the ...200818256208
synthesis and biological evaluation of inhibitors of thymidine monophosphate kinase from bacillus anthracis.nineteen lipophilic thymidine phosphate-mimicking compounds were designed and synthesized as potential inhibitors of thymidine monophosphate kinase of bacillus anthracis, a gram-positive bacterium that causes anthrax. these thymidine analogues were substituted at the 5'-postion with sulfonamide-, amide-, (thio)urea-, or triazole groups, which served as lipophilic surrogates for phosphate. three of the tested compounds produced inhibition of b. anthracis sterne growth and/or thymidine monophospha ...200818260009
expression and characterization of aiia gene from bacillus subtilis bs-1.ahl-lactonase (aiia), a metallo-beta-lactamase produced by bacillus thuringiensis, bacillus cereus and bacillus anthracis, specifically hydrolyzes n-acyl-homoserine lactones (ahls) secreted by gram-negative bacteria and thereby attenuates the symptoms caused by plant pathogens. in this study, an aiia gene was cloned from bacillus subtilis bs-1 by pcr with a pair of degenerate primers. the deduced 250 amino acid sequence contained two small conserved regions, 103shlhfdh109 and 166tpghtpgh173, whi ...200818261893
degradation of circulating von willebrand factor and its regulator adamts13 implicates secreted bacillus anthracis metalloproteases in anthrax consumptive coagulopathy.pathology data from the anthrax animal models show evidence of significant increases in vascular permeability coincident with hemostatic imbalances manifested by thrombocytopenia, transient leucopenia, and aggressive disseminated intravascular coagulation. in this study we hypothesized that anthrax infection modulates the activity of von willebrand factor (vwf) and its endogenous regulator adamts13, which play important roles in hemostasis and thrombosis, including interaction of endothelial cel ...200818263586
killing of macrophages by anthrax lethal toxin: involvement of the n-end rule pathway.macrophages from certain inbred mouse strains are rapidly killed (< 90 min) by anthrax lethal toxin (lt). lt cleaves cytoplasmic mek proteins at 20 min and induces caspase-1 activation in sensitive macrophages at 50-60 min, but the mechanism of lt-induced death is unknown. proteasome inhibitors block lt-mediated caspase-1 activation and can protect against cell death, indicating that the degradation of at least one cellular protein is required for lt-mediated cell death. proteins can be degraded ...200818266992
anthrax lethal toxin induces cell death-independent permeability in zebrafish vasculature.vascular dysfunction has been reported in human cases of anthrax, in mammalian models of bacillus anthracis, and in animals injected with anthrax toxin proteins. to examine anthrax lethal toxin effects on intact blood vessels, we developed a zebrafish model that permits in vivo imaging and evaluation of vasculature and cardiovascular function. vascular defects monitored in hundreds of embryos enabled us to define four stages of phenotypic progression leading to circulatory dysfunction. we demons ...200818268319
the effects of anthrax lethal factor on the macrophage proteome: potential activity on nitric oxide synthases.anthrax lethal factor (letx) is a critical virulence factor in toxin-challenged cells, as lethal factor (lf) cleaves mitogen-activated protein kinase kinases (mkks), inhibiting their activity. the physiological importance of this cleavage for macrophage cytolysis remains unclear, because similar proteolysis has been also observed in letx-resistant macrophages. here, we analyzed in vitro proteomic profiles of raw264.7 lysates treated with lf. in our experiments, neuronal no synthase (nnos) was fo ...200818269913
self-transfer and mobilisation capabilities of the pxo2-like plasmid pbt9727 from bacillus thuringiensis subsp. konkukian 97-27.recent characterisations of plasmids related to the anthrax virulence plasmids pxo1 and pxo2 in clinical isolates of bacillus cereus and bacillus thuringiensis have contributed to the emerging picture of a virulence-associated plasmid pool in the b. cereus sensu lato group. the family of pxo2-like plasmids includes the conjugative plasmid paw63 from the biopesticide strain b. thuringiensis subsp. kurstaki hd73 and the heretofore cryptic plasmid pbt9727 from the clinical strain b. thuringiensis s ...200818272219
efficient production and characterization of bacillus anthracis lethal factor and a novel inactive mutant rlfm-y236f.lethal factor (lf) is a 90kda zinc metalloprotease that plays an important role in the virulence of anthrax. recombinant lf (rlf) is an effective tool to study anthrax pathogenesis and treatment. in this study, the lf gene was cloned into the escherichia coli expression vector pgex-6p-1 and expressed as a gst fusion protein (gst-rlf) in e. coli bl21-codonplus (de3)-ril cells with 0.2mm iptg induction at 28 degrees c. the gst-rlf protein was purified and the gst-tag was then cleaved in a single s ...200818276157
renewable enzyme reactors based on beds of artificial gel antibodies.a novel approach is described for the synthesis of beds for enzyme reactors. the method is based on the use of artificial antibodies in the form of polyacrylamide gel particles with diameters around 0.1-0.3 mm. these gel particles mimic protein antibodies, raised in experimental animals, in the sense that they selectively recognize and adsorb only the protein present during the preparation of the "antibodies". the gel antibodies have several advantages over conventional protein antibodies, which ...200818280576
n-substituted 3-acetyltetramic acid derivatives as antibacterial agents.in order to expand the structure-activity relationship of tetramic acid molecules with structural similarity to the antibiotic reutericyclin, 22 compounds were synthesized and tested against a panel of clinically relevant bacteria. key structural changes on the tetramic acid core affected antibacterial activity. various compounds in the n-alkyl 3-acetyltetramic acid series exhibited good activity against gram-positive bacterial pathogens including bacillus anthracis, propionibacterium acnes, ent ...200818281930
nucleotide biosynthesis is critical for growth of bacteria in human blood.proliferation of bacterial pathogens in blood represents one of the most dangerous stages of infection. growth in blood serum depends on the ability of a pathogen to adjust metabolism to match the availability of nutrients. although certain nutrients are scarce in blood and need to be de novo synthesized by proliferating bacteria, it is unclear which metabolic pathways are critical for bacterial growth in blood. in this study, we identified metabolic functions that are essential specifically for ...200818282099
performance of an algorithm for assessing smallpox risk among patients with rashes that may be confused with smallpox.after the 2001 anthrax bioterror attacks, the centers for disease control and prevention developed an algorithm to evaluate patients rapidly for suspected smallpox. a prospective, multicenter study examined the performance of this algorithm in assessing patients with an acute, generalized vesicular or pustular rash (agvpr) admitted to emergency departments and inpatient units of 12 acute-care hospitals in 6 states. of 26,747 patients (3.5% of all admissions) with rashlike conditions screened, 89 ...200818284359
enhancement of antibody responses to bacillus anthracis protective antigen domain iv by use of calreticulin as a chimeric molecular adjuvant.the generation of protective humoral immune responses against the receptor-binding domain (domain iv) of protective antigen [pa(div)] of bacillus anthracis represents a plausible approach against anthrax toxin. in the current study, we have developed a naked dna vaccine encoding calreticulin (crt) linked to pa(div) of bacillus anthracis [crt/pa(div)]. we transfected a human embryonic kidney cell line (hek 293) with crt/pa(div) dna and performed western blotting and confocal microscopy analysis. ...200818285494
glycosyltransferase: a specific marker for the discrimination of bacillus anthracis from the bacillus cereus group.bacillus anthracis, the aetiological agent of anthrax, has been taxonomically classified with the bacillus cereus group, which comprises b. cereus, bacillus thuringiensis, bacillus mycoides, bacillus pseudomycoides and bacillus weihenstephanensis. although the pathogenesis and ecological manifestations may be different, b. anthracis shares a high degree of dna sequence similarity with its group member species. as a result, the discrimination of b. anthracis from its close relatives in the b. cer ...200818287289
binary actin-adp-ribosylating toxins and their use as molecular trojan horses for drug delivery into eukaryotic cells.binary bacterial toxins are unique ab-type toxins, composed of two non-linked proteins that act as a binding/translocation component and an enzyme component. all known actin-adp-ribosylating toxins from clostridia possess this binary structure. this toxin family is comprised of the prototypical clostridium botulinum c2 toxin, clostridium perfringens iota toxin, clostridium difficile cdt, and clostridium spiroforme toxin. once in the cytosol of host cells, these toxins transfer an adp-ribose moie ...200818289001
discovery and development of anthrax lethal factor metalloproteinase inhibitors.anthrax is caused by infection with bacillus anthracis, a spore forming, rod-shaped, encapsulated gram positive bacteria. the disease manifests itself in distinct ways depending on the route of entry of infective bacterial spores: cutaneous, inhalational, and gastrointestinal. though rare in humans, inhalational anthrax has become a major concern due to the capacity for spores to be weaponized. the limited success of antibiotic therapy has motivated investigation of complementary therapeutic str ...200818289054
plasmid-based vaccination with candidate anthrax vaccine antigens induces durable type 1 and type 2 t-helper immune responses.the current anthrax vaccine imparts protective immunity by generating a humoral immune response against a single antigen, the pa exotoxin subunit. while this response neutralizes the two anthrax exotoxins and protects the recipient from toxin-related mortality, the recipient is not protected from spore germination, infection, and/or bacteremia. moreover, protective immunity against pa must be generated via a lengthy injection schedule and maintained by a yearly booster. in an effort to improve u ...200818166249
vaccines: countering anthrax: vaccines and immunoglobulins.anthrax spores rank as the leading threat among bioweapons. this article reviews the accumulated evidence for immunization, either active or passive, to counter the malicious release of anthrax spores. the key protective factor in current anthrax vaccines for humans is a protein called protective antigen, which allows ingress of toxins into cells. the us vaccine is licensed to prevent anthrax, regardless of the route of exposure. its dosing schedule is cumbersome and somewhat painful (shortcomin ...200818171228
inhibition of mapk kinase signaling pathways suppressed renal cell carcinoma growth and angiogenesis in vivo.the mitogen-activated protein kinase (mapk) signaling pathways play essential roles in cell proliferation and differentiation. recent studies also show the activation of mapk signaling pathways in tumorigenesis, metastasis, and angiogenesis of multiple human malignancies, including renal cell carcinoma (rcc). to assess the role of this pathway in regulating the proliferation and survival of rcc cells, we first examined the expression of mapk kinase (mkk) and mapk in clear cell rcc and confirmed ...200818172299
severe febrile respiratory illnesses as a cause of mass critical care.febrile respiratory illnesses with respiratory failure are one of the most common reasons for admission to the intensive care unit. most causes of febrile respiratory illness are bacterial and viral agents of community-acquired pneumonia. however, a small number of rare and highly contagious agents can initially present as febrile respiratory illnesses, which can lead to an epidemic that can greatly impact the health care system. this impact includes sustained mass critical care, with potential ...200818173859
the conformational plasticity of calmodulin upon calcium complexation gives a model of its interaction with the oedema factor of bacillus anthracis.we analyzed the conformational plasticity of calmodulin (cam) when it is bound to the oedema factor (ef) of bacillus anthracis and its response to calcium complexation with molecular dynamics (md) simulations. the ef-cam complex was simulated during 15 ns for three different levels of calcium bound to cam. they were respectively no calcium ion (ef-(apo-cam)), two calcium ions bound to the c-terminal domain of cam (ef-(2ca-cam)), and four calcium ions bound to cam (ef-(4ca-cam)). calculations wer ...200818175311
gtp-dependent polymerization of the tubulin-like repx replication protein encoded by the pxo1 plasmid of bacillus anthracis.repx protein encoded by the pxo1 plasmid of bacillus anthracis is required for plasmid replication. repx harbours the tubulin signature motif and contains limited amino acid sequence homology to the bacterial cell division protein ftsz. although replication proteins are not known to polymerize, here we show by electron microscopy that repx undergoes gtp-dependent polymerization into long filaments. repx filaments assembled in the presence of gtpgammas were more stable than those assembled in the ...200818179418
mechanisms of pathogenesis and the evolution of parasite virulence.when studying how much a parasite harms its host, evolutionary biologists turn to the evolutionary theory of virulence. that theory has been successful in predicting how parasite virulence evolves in response to changes in epidemiological conditions of parasite transmission or to perturbations induced by drug treatments. the evolutionary theory of virulence is, however, nearly silent about the expected differences in virulence between different species of parasite. why, for example, is anthrax s ...200818179516
detection of large plasmids from the bacillus cereus group.the members of the bacillus cereus group, bacillus anthracis, bacillus thuringiensis, and b. cereus senso stricto, are largely defined by their content of large plasmids, which encode major virulence factors. here we offer an easy, fast, and reliable protocol for the isolation and detection of large plasmids up to the size of at least 350kb. furthermore, using this method, we report that bacillus mycoides contain large plasmids.200818179822
inhibition of anthrax lethal toxin-induced cytolysis of raw264.7 cells by celastrol.bacillus anthracis is the bacterium responsible for causing anthrax. the ability of b. anthracis to cause disease is dependent on a secreted virulence factor, lethal toxin, that promotes survival of the bacteria in the host by impairing the immune response. a well-studied effect of lethal toxin is the killing of macrophages, although the molecular mechanisms involved have not been fully characterized.200818183301
single-shot detection of bacterial endospores via coherent raman spectroscopy.recent advances in coherent raman spectroscopy hold exciting promise for many potential applications. for example, a technique, mitigating the nonresonant four-wave-mixing noise while maximizing the raman-resonant signal, has been developed and applied to the problem of real-time detection of bacterial endospores. after a brief review of the technique essentials, we show how extensions of our earlier experimental work [pestov d, et al. (2007) science 316:265-268] yield single-shot identification ...200818184801
a structural basis for the allosteric regulation of non-hydrolysing udp-glcnac 2-epimerases.the non-hydrolysing bacterial udp-n-acetylglucosamine 2-epimerase (udp-glcnac 2-epimerase) catalyses the conversion of udp-glcnac into udp-n-acetylmannosamine, an intermediate in the biosynthesis of several cell-surface polysaccharides. this enzyme is allosterically regulated by its substrate udp-glcnac. the structure of the ternary complex between the bacillus anthracis udp-glcnac 2-epimerase, its substrate udp-glcnac and the reaction intermediate udp, showed direct interactions between udp and ...200818188181
spo0b of bacillus anthracis - a protein with pleiotropic functions.spo0b is an important component of the phosphorelay signal transduction pathway, the pathway involved in the initiation of sporulation in bacillus subtilis. bioinformatic, phylogenetic and biochemical studies showed that spo0b of bacillus anthracis has evolved from citrate/malate kinases. during the course of evolution, spo0b has retained the characteristic histidine kinase boxes h, n, f, g(1) and g(2), and has acquired nucleotide-binding domains, walker a and walker b, of atpases. owing to the ...200818190531
selection and evaluation of the immunogenicity of protective antigen mutants as anthrax vaccine candidates.protective antigen (pa) is a central component of anthrax toxin and a major antigen in anthrax vaccines. however, the use of native pa as a vaccine is not optimal. if administered to people who have been freshly exposed to anthrax, pa may actually aid in anthrax toxin formation and thus may pose a serious safety concern for postexposure vaccination applications. a non-functional pa mutant may be a much safer alternative. to identify an improved anthrax vaccine antigen, we examined four non-funct ...200818192092
bacillus anthracis spore suspensions: determination of stability and comparison of enumeration techniques.to determine the stability and variability in concentration of spore suspensions of bacillus anthracis (ba) spore suspensions by comparing different methods of enumeration and to detect changes, if any, under different storage conditions.200818194254
nasal immunization with the mixture of pa63, lf, and a pga conjugate induced strong antibody responses against all three antigens.a new generation anthrax vaccine is expected to target not only the anthrax protective antigen (pa) protein, but also other virulent factors of bacillus anthracis. it is also expected to be amenable for rapid mass immunization of a large number of people. this study aimed to address these needs by designing a prototypic triantigen nasal anthrax vaccine candidate that contained a truncated pa (rpa63), the anthrax lethal factor (lf), and the capsular poly-gamma-d-glutamic acid (gammadpga) as the a ...200818194342
maturation modulates caspase-1-independent responses of dendritic cells to anthrax lethal toxin.anthrax lethal toxin (lt) contributes to the immune evasion strategy of bacillus anthracis by impairing the function of cells of the immune system, such as macrophages and dendritic cells (dcs). macrophages from certain inbred mice strains undergo rapid death upon lt treatment mediated by caspase-1 activation dependent on nalp1b, an inflammasome component. rapid lt-induced death is however, not observed in macrophages from human and many mouse strains. here, we focused on the responses of variou ...200818194483
estimating the joint disease outbreak-detection time when an automated biosurveillance system is augmenting traditional clinical case finding.the goals of automated biosurveillance systems are to detect disease outbreaks early, while exhibiting few false positives. evaluation measures currently exist to estimate the expected detection time of biosurveillance systems. researchers also have developed models that estimate clinician detection of cases of outbreak diseases, which is a process known as clinical case finding. however, little research has been done on estimating how well biosurveillance systems augment traditional outbreak de ...200818194876
detection of bacillus anthracis spore germination in vivo by bioluminescence imaging.we sought to visualize the site of bacillus anthracis spore germination in vivo. for that purpose, we constructed a reporter plasmid with the lux operon under control of the spore small acid-soluble protein b (sspb) promoter. in b. subtilis, sspb-driven synthesis of luciferase during sporulation results in incorporation of the enzyme in spores. we observed that b. anthracis sterne transformed with our sspbp::lux plasmid was only luminescent during germination. in contrast, sterne transformed wit ...200818195028
in vivo fate and distribution of poly-gamma-d-glutamic acid, the capsular antigen from bacillus anthracis.bacillus anthracis is surrounded by an antiphagocytic capsule composed of poly-gamma-d-glutamic acid (gammadpga). bacterial and fungal capsular polysaccharides are shed into body fluids in large amounts during infection. the goal of our study was to examine the in vivo fate and distribution of the gammadpga capsular polypeptide. mice were injected via the intravenous route with various amounts of purified gammadpga. blood, urine, and various organs were harvested at different times after treatme ...200818195035
preattack vaccination against anthrax may be cost-effective in certain populations. 200818195210
adverse events associated with prolonged antibiotic use.the infectious diseases society of america and us cdc recommend 60 days of ciprofloxacin, doxycycline, or amoxicillin for anthrax prophylaxis. it is not possible to determine severe adverse drug event (ade) risks from the few people thus far exposed to anthrax prophylaxis. this study's objective was to estimate risks of severe ades associated with long-term ciprofloxacin, doxycycline, and amoxicillin exposure using three large databases: one electronic medical record (general practice research d ...200818215001
plant-pathogenic streptomyces species produce nitric oxide synthase-derived nitric oxide in response to host signals.nitric oxide (no) is a potent intercellular signal for defense, development, and metabolism in animals and plants. in mammals, highly regulated nitric oxide synthases (noss) generate no. nos homologs exist in some prokaryotes, but direct evidence for no production by these proteins has been lacking. here, we demonstrate that a nos in plant-pathogenic streptomyces species produces diffusible no. nos-dependent no production increased in response to cellobiose, a plant cell wall component, and occu ...200818215772
bacillus anthracis-derived nitric oxide is essential for pathogen virulence and survival in macrophages.phagocytes generate nitric oxide (no) and other reactive oxygen and nitrogen species in large quantities to combat infecting bacteria. here, we report the surprising observation that in vivo survival of a notorious pathogen-bacillus anthracis-critically depends on its own no-synthase (bnos) activity. anthrax spores (sterne strain) deficient in bnos lose their virulence in an a/j mouse model of systemic infection and exhibit severely compromised survival when germinating within macrophages. the m ...200818215992
the integrin mac-1 (cr3) mediates internalization and directs bacillus anthracis spores into professional phagocytes.anthrax, a disease caused by bacillus anthracis, affects animals and humans. because the inert spore is the infectious form of the organism that first contacts the potential host, the interaction between the host and spore exosporium is vital to the initiation of disease. here, we demonstrate that the integrin mac-1 is essential for the recognition of the major exosporium protein bcla by phagocytic cells. expression of mac-1, but not p150/95, in cho cells markedly enhanced infection with sterne ...200818216258
in vitro assembly studies of ftsz/tubulin-like proteins (tubz) from bacillus plasmids: evidence for a capping mechanism.proteins with a weak sequence similarity to tubulin and ftsz are expressed from large plasmids of bacillus anthracis and bacillus thuringiensis and are probably involved in plasmid segregation. previously designated repx and tubz, we designate them here as tubz-ba and tubz-bt. we have expressed and purified the proteins for in vitro studies. tubz-ba and tubz-bt share only 21% amino acid identity, but they have remarkably similar biochemical properties. they both assemble into two-stranded filame ...200818198178
analysis of bacillus globigii spores by ce.it is imperative in today's world that harmful airborne or solution-based microbes can be detected quickly and efficiently. bacillus globigii (bg) spores are used as a simulant for bacillus anthracis (ba) due to their similar shape, size, and cellular makeup. the utility of ce to separate and detect low levels of bg spore concentrations will be evaluated. to differentiate spores from background particulates, several dyes, including fluorescamine, c-10, nn-127, red-1c, and indocyanine green (icg) ...200818203249
serum igg antibody response to the protective antigen (pa) of bacillus anthracis induced by anthrax vaccine adsorbed (ava) among u.s. military personnel.the seroconversion rates and geometric mean concentrations (gmc) of igg anti-pa for stored sera from u.s. military personnel immunized 3, 4, and 6 times with the u.s. licensed anthrax vaccine adsorbed were studied. anti-pa igg concentrations were measured by elisa. all 246 vaccinees had low but detectable pre-immunization anti-pa igg (gmc 1.83 microg/ml). three doses elicited a gmc of 59.92 microg/ml and a seroconversion rate of 85.3%, four doses elicited a gmc of 157.44 microg/ml and 67.9% and ...200818206278
treatment of experimental anthrax with recombinant capsule depolymerase.bacillus anthracis produces an antiphagocytic gamma-linked poly-d-glutamic acid capsule that is required for virulence. capsule depolymerase (capd) is a membrane-associated poly-gamma-glutamate-specific depolymerase encoded on the b. anthracis capsule plasmid, px02, that is reported to contribute to virulence by anchoring the capsule to the peptidoglycan and partially degrading high-molecular-weight capsule from the bacterial surface. we previously demonstrated that treatment with capd effective ...200818160516
cell wall carbohydrate compositions of strains from the bacillus cereus group of species correlate with phylogenetic relatedness.members of the bacillus cereus group contain cell wall carbohydrates that vary in their glycosyl compositions. recent multilocus sequence typing (mlst) refined the relatedness of b. cereus group members by separating them into clades and lineages. based on mlst, we selected several b. anthracis, b. cereus, and b. thuringiensis strains and compared their cell wall carbohydrates. the cell walls of different b. anthracis strains (clade 1/anthracis) were composed of glucose (glc), galactose (gal), n ...200817981984
supercat: a supertree database for combined and integrative multilocus sequence typing analysis of the bacillus cereus group of bacteria (including b. cereus, b. anthracis and b. thuringiensis).the bacillus cereus group of bacteria is an important group including mammalian and insect pathogens, such as b. anthracis, the anthrax bacterium, b. thuringiensis, used as a biological pesticide and b. cereus, often involved in food poisoning incidents. to characterize the population structure and epidemiology of these bacteria, five separate multilocus sequence typing (mlst) schemes have been developed, which makes results difficult to compare. therefore, we have developed a database that comp ...200817982177
discrimination of bacillus anthracis and closely related microorganisms by analysis of 16s and 23s rrna with oligonucleotide microarray.analysis of 16s rrna sequences is a commonly used method for the identification and discrimination of microorganisms. however, the high similarity of 16s and 23s rrna sequences of bacillus cereus group organisms (up to 99-100%) and repeatedly failed attempts to develop molecular typing systems that would use dna sequences to discriminate between species within this group have resulted in several suggestions to consider b. cereus and b. thuringiensis, or these two species together with b. anthrac ...200817950718
carbohydrate-based experimental therapeutics for cancer, hiv/aids and other diseases.this review, primarily for general readers, briefly presents experimental approaches to therapeutics of cancer, hiv/aids and various other diseases based on advances in glycobiology and glycochemistry. experimental cancer and hiv/aids vaccines are being developed in attempts to overcome weak immunological responses to carbohydrate-rich surface antigens using carriers, adjuvants and novel carbohydrate antigen constructs. current carbohydrate-based vaccines are used for typhus, pneumonia, meningit ...200817963823
development and implementation of a single-chain fv antibody for specific detection of bacillus anthracis spores.a single-chain fv (scfv) antibody was developed and applied for efficient and specific detection of bacillus anthracis spores. the antibody was isolated from a phage display library prepared from spleens of mice immunized with a water-soluble extract of the outer membrane of the b. anthracis spore (exosporium). the library (7 x 10(6) pfu) was biopanned against live, native b. anthracis atcc delta14185 spores suspended in solution, resulting in the isolation of a unique soluble scfv antibody. the ...200817965209
emilins interact with anthrax protective antigen and inhibit toxin action in vitro.the informational spectrum method (ism) is a virtual spectroscopy method for the fast analysis of potential protein-protein relationships. by applying the ism approach to the genebank protein database the vascular proteins emilin1 (elastin microfibril interface located protein), emilin2, mmn1, and mmn2 were identified as additional anthrax pa antigen interacting molecules. this virtual molecular interaction was formally proven by solid phase assays using recombinant proteins. the interaction is ...200817988845
bacterial pore-forming toxins: the (w)hole story?pore-forming toxins (pfts) are the most common class of bacterial protein toxins and constitute important bacterial virulence factors. the mode of action of pft is starting to be better understood. in contrast, little is known about the cellular response to this threat. recent studies reveal that cells do not just swell and lyse, but are able to sense and react to pore formation, mount a defense, even repair the damaged membrane and thus survive. these responses involve a variety of signal-trans ...200817989920
selection and characterization of human antibodies neutralizing bacillus anthracis toxin.a less than adequate therapeutic plan for the treatment of anthrax in the 2001 bioterrorism attacks has highlighted the importance of developing alternative or complementary therapeutic approaches for biothreat agents. in these regards passive immunization possesses several important advantages over active vaccination and the use of antibiotics, as it can provide immediate protection against bacillus anthracis. herein, we report the selection and characterization of several human monoclonal neut ...200818023190
coplot: a tool for visualizing multivariate data in medicine.many critical questions in medicine require the analysis of complex multivariate data, often from large data sets describing numerous variables for numerous subjects. in this paper, we describe coplot, a tool for visualizing multivariate data in medicine. coplot is an adaptation of multidimensional scaling (mds) that addresses several key limitations of mds, namely that mds maps do not allow for visualization of both observations and variables simultaneously and that the axes on an mds map have ...200817972340
matrix metalloproteinase-activated anthrax lethal toxin demonstrates high potency in targeting tumor vasculature.anthrax lethal toxin (lt), a virulence factor secreted by bacillus anthracis, is selectively toxic to human melanomas with the braf v600e activating mutation because of its proteolytic activities toward the mitogen-activated protein kinase kinases (meks). to develop lt variants with lower in vivo toxicity and high tumor specificity, and therefore greater potential for clinical use, we generated a mutated lt that requires activation by matrix metalloproteinases (mmps). this engineered toxin was l ...200817974567
a novel immunogenic spore coat-associated protein in bacillus anthracis: characterization via proteomics approaches and a vector-based vaccine system.new generation anthrax vaccines have been actively explored with the aim of enhancing efficacies and decreasing undesirable side effects that could be caused by licensed vaccines. targeting novel antigens and/or eliminating the requirements for multiple needle injections and adjuvants are major objectives in the development of new anthrax vaccines. using proteomics approaches, we identified a spore coat-associated protein (scap) in bacillus anthracis. an escherichia coli vector-based vaccine sys ...200818029197
neutralizing activity of vaccine-induced antibodies to two bacillus anthracis toxin components, lethal factor and edema factor.anthrax vaccine adsorbed (ava; biothrax), the current fda-licensed human anthrax vaccine, contains various amounts of the three anthrax toxin components, protective antigen (pa), lethal factor (lf), and edema factor (ef). while antibody to pa is sufficient to mediate protection against anthrax in animal models, it is not known if antibodies to lf or ef contribute to protection in humans. toxin-neutralizing activity was evaluated in sera from ava-vaccinated volunteers, all of whom had antibody re ...200818032590
transcriptional profiling of murine organ genes in response to infection with bacillus anthracis ames spores.bacillus anthracis is the gram-positive, spore-forming etiological agent of anthrax, an affliction studied because of its importance as a potential bioweapon. although in vitro transcriptional responses of macrophages to either spore or anthrax toxins have been previously reported, little is known regarding the impact of infection on gene expression in host tissues. we infected swiss-webster mice intranasally with 5 ld(50) of b. anthracis-virulent ames spores and observed the global transcriptio ...200818037264
inhibiting dihydrodipicolinate synthase across species: towards specificity for pathogens?dihydrodipicolinate synthase (dhdps) is a key enzyme in lysine biosynthesis and an important antibiotic target. the specificity of a range of heterocyclic product analogues against dhdps from three pathogenic species, bacillus anthracis, mycobacterium tuberculosis and methicillin-resistant staphylococcus aureus, and the evolutionarily related n-acetylneuraminate lyase, has been determined. the results suggest that the development of species-specific inhibitors of dhdps as potential antibacterial ...200818054225
rapid/sustained anti-anthrax passive immunity mediated by co-administration of ad/aav.achieving both immediate and sustained protection against diseases caused by bacterial toxins and extracellular pathogens is a challenge in developing biodefense therapeutics. we hypothesized that a single co-administration of an adenovirus (ad) vector and an adeno-associated virus (aav) vector, both expressing a pathogen-specific monoclonal antibody, would provide rapid, persistent passive immunotherapy against the pathogen. in order to test this strategy, we used the lethal toxin of bacillus a ...200818059375
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