bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antibiotic Resistance Markers in Burkholderia pseudomallei Strain Bp1651 Identified by Genome Sequence Analysis
Authors: Bugrysheva Julia V. , Sue David , Gee Jay E. , Elrod Mindy G. , Hoffmaster Alex R. , Randall Linnell B. , Chirakul Sunisa , Tuanyok Apichai , Schweizer Herbert P. , Weigel Linda M. 
Published: April 2017

ABSTRACT

Burkholderia pseudomallei
Bp1651 is resistant to several classes of antibiotics that are usually effective for treatment of melioidosis, including tetracyclines, sulfonamides, and β-lactams such as penicillins (amoxicillin-clavulanic acid), cephalosporins (ceftazidime), and carbapenems (imipenem and meropenem). We sequenced, assembled, and annotated the Bp1651 genome and analyzed the sequence using comparative genomic analyses with susceptible strains, keyword searches of the annotation, publicly available antimicrobial resistance prediction tools, and published reports. More than 100 genes in the Bp1651 sequence were identified as potentially contributing to antimicrobial resistance. Most notably, we identified three previously uncharacterized point mutations in
penA
, which codes for a class A β-lactamase and was previously implicated in resistance to β-lactam antibiotics. The mutations result in amino acid changes T147A, D240G, and V261I. When individually introduced into select agent-excluded
B. pseudomallei
strain Bp82, D240G was found to contribute to ceftazidime resistance and T147A contributed to amoxicillin-clavulanic acid and imipenem resistance. This study provides the first evidence that mutations in
penA
may alter susceptibility to carbapenems in
B. pseudomallei
. Another mutation of interest was a point mutation affecting the dihydrofolate reductase gene
folA
, which likely explains the trimethoprim resistance of this strain. Bp1651 was susceptible to aminoglycosides likely because of a frameshift in the
amrB
gene, the transporter subunit of the AmrAB-OprA efflux pump. These findings expand the role of
penA
to include resistance to carbapenems and may assist in the development of molecular diagnostics that predict antimicrobial resistance and provide guidance for treatment of melioidosis.
Rifabutin Is Active against Mycobacterium abscessus Complex
Authors: Aziz Dinah Binte , Low Jian Liang , Wu Mu-Lu , Gengenbacher Martin , Teo Jeanette W. P. , Dartois Véronique , Dick Thomas 
Published: April 2017

ABSTRACT

Lung infections caused by
Mycobacterium abscessus
are emerging as a global threat to individuals with cystic fibrosis and to other patient groups. Recent evidence for human-to-human transmission worsens the situation.
M. abscessus
is an intrinsically multidrug-resistant pathogen showing resistance to even standard antituberculosis drugs, such as rifampin. Here, our objective was to identify existing drugs that may be employed for the treatment of
M. abscessus
lung disease. A collection of more than 2,700 approved drugs was screened at a single-point concentration against an
M. abscessus
clinical isolate. Hits were confirmed with fresh solids in dose-response experiments. For the most attractive hit, growth inhibition and bactericidal activities against reference strains of the three
M. abscessus
subspecies and a collection of clinical isolates were determined. Surprisingly, the rifampin derivative rifabutin had MICs of 3 ± 2 μM (3 μg/ml) against the screening strain, the reference strains
M. abscessus
subsp.
abscessus
ATCC 19977,
M. abscessus
subsp.
bolletii
CCUG 50184-T, and
M. abscessus
subsp.
massiliense
CCUG 48898-T, as well as against a collection of clinical isolates. Furthermore, rifabutin was active against clarithromycin-resistant strains. In conclusion, rifabutin, in contrast to rifampin, is active against the
Mycobacterium abscessus
complex bacteria
in vitro
and may be considered for treatment of
M. abscessus
lung disease.
In Vivo
Pharmacokinetics and Pharmacodynamics of ZTI-01 (Fosfomycin for Injection) in the Neutropenic Murine Thigh Infection Model against Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa
Authors: Lepak Alexander J. , Zhao Miao , VanScoy Brian , Taylor Daniel S. , Ellis-Grosse Evelyn , Ambrose Paul G. , Andes David R. 
Published: April 2017

ABSTRACT

Fosfomycin is a broad-spectrum agent with activity against Gram-positive and Gram-negative bacteria, including drug-resistant strains, such as extended-spectrum-beta-lactamase (ESBL)-producing and carbapenem-resistant (CR) Gram-negative rods. In the present study, the pharmacokinetic/pharmacodynamic (PK/PD) activity of ZTI-01 (fosfomycin for injection) was evaluated in the neutropenic murine thigh infection model against 5
Escherichia coli
, 3
Klebsiella pneumoniae
, and 2
Pseudomonas aeruginosa
strains, including a subset with ESBL and CR phenotypes. The pharmacokinetics of ZTI-01 were examined in mice after subcutaneous administration of 3.125, 12.5, 50, 200, 400, and 800 mg/kg of body weight. The half-life ranged from 0.51 to 1.1 h, area under the concentration-time curve (AUC
0–∞
) ranged from 1.4 to 87 mg · h/liter, and maximum concentrations ranged from 0.6 to 42.4 mg/liter. Dose fractionation demonstrated the AUC/MIC ratio to be the PK/PD index most closely linked to efficacy (
R
2
= 0.70). Net stasis and bactericidal activity were observed against all strains. Net stasis was observed at 24-h AUC/MIC ratio values of 24, 21, and 15 for
E. coli
,
K.
,
pneumoniae
and
P. aeruginosa
, respectively. For the
Enterobacteriaceae
group, stasis was noted at mean 24-h AUC/MIC ratio targets of 23 and 1-log kill at 83. Survival in mice infected with
E. coli
145 was maximal at 24-h AUC/MIC ratio exposures of 9 to 43, which is comparable to the stasis exposures identified in the PK/PD studies. These results should prove useful for the design of clinical dosing regimens for ZTI-01 in the treatment of serious infections due to
Enterobacteriaceae
and
Pseudomonas
.
A Topical Hydrogel with Deferiprone and Gallium-Protoporphyrin Targets Bacterial Iron Metabolism and Has Antibiofilm Activity
Authors: Richter Katharina , Thomas Nicky , Claeys Jolien , McGuane Jonathan , Prestidge Clive A. , Coenye Tom , Wormald Peter-John , Vreugde Sarah 
Published: April 2017

ABSTRACT

Many infectious diseases are associated with multidrug-resistant (MDR) bacteria residing in biofilms that require high antibiotic concentrations. While oral drug delivery is frequently ineffective, topical treatments have the potential to deliver higher drug concentrations to the infection site while reducing systemic side effects. This study determined the antibiofilm activity of a surgical wound gel loaded with the iron chelator deferiprone (Def) and the heme analogue gallium-protoporphyrin (GaPP), alone and in combination with ciprofloxacin. Activity against MDR
Staphylococcus aureus
,
Staphylococcus epidermidis
,
Pseudomonas aeruginosa
, and
Acinetobacter johnsonii
biofilms was assessed in the colony biofilm and artificial wound model by enumeration of CFU and correlative light/electron microscopy. While
Staphylococcus
biofilms were equally susceptible to GaPP and Def-GaPP gels (log
10
reduction of 3.8 and 3.7, respectively), the Def-GaPP combination was crucial for significant activity against
P. aeruginosa
biofilms (log
10
reduction of 1.3 for GaPP and 3.3 for Def-GaPP). When Def-GaPP gel was combined with ciprofloxacin, the efficacy exceeded the activity of the individual compounds. Def-GaPP delivered in a surgical wound gel showed significant antibiofilm activity against different MDR strains and could enhance the gel's wound-healing properties. Moreover, Def-GaPP indicated a potentiation of ciprofloxacin. This antibiofilm strategy has potential for clinical utilization as a therapy for topical biofilm-related infections.
Attenuated Phenotype of a Recent House Finch-Associated Mycoplasma gallisepticum Isolate in Domestic Poultry
Authors: Pflaum K. , Tulman E. R. , Beaudet J. , Liao X. , Dhondt K. V. , Dhondt A. A. , Hawley D. M. , Ley D. H. , Kerr K. M. , Geary S. J. 
Published: April 2017

ABSTRACT

Mycoplasma gallisepticum
, known primarily as a respiratory pathogen of domestic poultry, has emerged since 1994 as a significant pathogen of the house finch (
Haemorhous
mexicanus
) causing severe conjunctivitis and mortality. House finch-associated
M. gallisepticum
(HFMG) spread rapidly and increased in virulence for the finch host in the eastern United States. In the current study, we assessed virulence in domestic poultry with two temporally distant, and yet geographically consistent, HFMG isolates which differ in virulence for house finches—Virginia 1994 (VA1994), the index isolate of the epidemic, and Virginia 2013 (VA2013), a recent isolate of increased house finch virulence. Here we report a significant difference between VA1994 and VA2013 in their levels of virulence for chickens; notably, this difference correlated inversely to the difference in their levels of virulence for house finches. VA1994, while moderately virulent in house finches, displayed significant virulence in the chicken respiratory tract. VA2013, while highly virulent in the house finch, was significantly attenuated in chickens relative to VA1994, displaying less-severe pathological lesions in, and reduced bacterial recovery from, the respiratory tract. Overall, these data indicate that a recent isolate of HFMG is greatly attenuated in the chicken host relative to the index isolate, notably demonstrating a virulence phenotype in chickens inversely related to that in the finch host.
Albumin, in the Presence of Calcium, Elicits a Massive Increase in Extracellular Bordetella Adenylate Cyclase Toxin
Authors: Gonyar Laura A. , Gray Mary C. , Christianson Gregory J. , Mehrad Borna , Hewlett Erik L. 
Published: April 2017

ABSTRACTPertussis (whooping cough), caused byBordetella pertussis, is resurging in the United States and worldwide. Adenylate cyclase toxin (ACT) is a critical factor in establishing infection withB. pertussisand acts by specifically inhibiting the response of myeloid leukocytes to the pathogen. We report here that serum components, as discovered during growth in fetal bovine serum (FBS), elicit a robust increase in the amount of ACT, and ≥90% of this ACT is localized to the supernatant, unlike growth without FBS, in which ≥90% is associated with the bacterium. We have found that albumin, in the presence of physiological concentrations of calcium, acts specifically to enhance the amount of ACT and its localization to the supernatant. Respiratory secretions, which contain albumin, promote an increase in amount and localization of active ACT that is comparable to that elicited by serum and albumin. The response to albumin is not mediated through regulation of ACT at the transcriptional level or activation of the Bvg two-component system. As further illustration of the specificity of this phenomenon, serum collected from mice that lack albumin does not stimulate an increase in ACT. These data, demonstrating that albumin and calcium act synergistically in the host environment to increase production and release of ACT, strongly suggest that this phenomenon reflects a novel host-pathogen interaction that is central to infection withB. pertussisand otherBordetellaspecies.
Host Resistance to Plasmodium-Induced Acute Immune Pathology Is Regulated by Interleukin-10 Receptor Signaling
Authors: Claser Carla , De Souza J. Brian , Thorburn Samuel G. , Grau Georges Emile , Riley Eleanor M. , Rénia Laurent , Hafalla Julius C. R. 
Published: April 2017

ABSTRACTThe resolution of malaria infection is dependent on a balance between proinflammatory and regulatory immune responses. While early effector T cell responses are required for limiting parasitemia, these responses need to be switched off by regulatory mechanisms in a timely manner to avoid immune-mediated tissue damage. Interleukin-10 receptor (IL-10R) signaling is considered to be a vital component of regulatory responses, although its role in host resistance to severe immune pathology during acute malaria infections is not fully understood. In this study, we have determined the contribution of IL-10R signaling to the regulation of immune responses duringPlasmodium bergheiANKA-induced experimental cerebral malaria (ECM). We show that antibody-mediated blockade of the IL-10R duringP. bergheiANKA infection in ECM-resistant BALB/c mice leads to amplified T cell activation, higher serum gamma interferon (IFN-γ) concentrations, enhanced intravascular accumulation of both parasitized red blood cells and CD8+T cells to the brain, and an increased incidence of ECM. Importantly, the pathogenic effects of IL-10R blockade duringP. bergheiANKA infection were reversible by depletion of T cells and neutralization of IFN-γ. Our findings underscore the importance of IL-10R signaling in preventing T-cell- and cytokine-mediated pathology during potentially lethal malaria infections.
The Histidine Residue of QseC Is Required for Canonical Signaling between QseB and PmrB in Uropathogenic Escherichia coli
Authors: Breland Erin J. , Zhang Ellisa W. , Bermudez Tomas , Martinez Charles R. , Hadjifrangiskou Maria 
Published: April 2017

ABSTRACT

Two-component systems are prototypically comprised of a histidine kinase (sensor) and a response regulator (responder). The sensor kinases autophosphorylate at a conserved histidine residue, acting as a phosphodonor for subsequent phosphotransfer to and activation of a cognate response regulator. In rare cases, the histidine residue is also essential for response regulator dephosphorylation via a reverse-phosphotransfer reaction. In this work, we present an example of a kinase that relies on reverse phosphotransfer to catalyze the dephosphorylation of its cognate partner. The QseC sensor kinase is conserved across several Gram-negative pathogens; its interaction with its cognate partner QseB is critical for maintaining pathogenic potential. Here, we demonstrate that QseC-mediated dephosphorylation of QseB occurs via reverse phosphotransfer. In previous studies, we demonstrated that, in uropathogenic
Escherichia coli
, exposure to high concentrations of ferric iron (Fe
3+
) stimulates the PmrB sensor kinase. This stimulation, in turn, activates the cognate partner, PmrA, and noncognate QseB to enhance tolerance to polymyxin B. We demonstrate that in the absence of signal, kinase-inactive QseC variants, in which the H246 residue was changed to alanine (A) aspartate (D) or leucine (L), rescued a Δ
qseC
deletion mutant, suggesting that QseC can control QseB activation via a mechanism that is independent of reverse phosphotransfer. However, in the presence of Fe
3+
, the same QseC variants were unable to mediate a wild-type stimulus response, indicating that QseC-mediated dephosphorylation is required for maintaining proper QseB-PmrB-PmrA interactions.

IMPORTANCE
Two-component signaling networks constitute one of the predominant methods by which bacteria sense and respond to their changing environments. Two-component systems allow bacteria to thrive and survive in a number of different environments, including within a human host. Uropathogenic
Escherichia coli
, the causative agent of urinary tract infections, rely on two interacting two-component systems, QseBC and PmrAB, to induce intrinsic resistance to the colistin antibiotic polymyxin B, which is a last line of defense drug. The presence of one sensor kinase, QseC, is required to regulate the interaction between the other sensor kinase, PmrB and the response regulators from both systems, QseB and PmrA, effectively creating a “four-component” system required for virulence. Understanding the important role of the sensor kinase QseC will provide insight into additional ways to therapeutically target uropathogens that harbor these signaling systems.
The SPOR Domain, a Widely Conserved Peptidoglycan Binding Domain That Targets Proteins to the Site of Cell Division
Authors: Yahashiri Atsushi , Jorgenson Matthew A. , Weiss David S. 
Published: April 2017

ABSTRACT
Sporulation-related repeat (SPOR) domains are small peptidoglycan (PG) binding domains found in thousands of bacterial proteins. The name “SPOR domain” stems from the fact that several early examples came from proteins involved in sporulation, but SPOR domain proteins are quite diverse and contribute to a variety of processes that involve remodeling of the PG sacculus, especially with respect to cell division. SPOR domains target proteins to the division site by binding to regions of PG devoid of stem peptides (“denuded” glycans), which in turn are enriched in septal PG by the intense, localized activity of cell wall amidases involved in daughter cell separation. This targeting mechanism sets SPOR domain proteins apart from most other septal ring proteins, which localize via protein-protein interactions. In addition to SPOR domains, bacteria contain several other PG-binding domains that can exploit features of the cell wall to target proteins to specific subcellular sites.
Association of the Cold Shock DEAD-Box RNA Helicase RhlE to the RNA Degradosome in Caulobacter crescentus
Authors: Aguirre Angel A. , Vicente Alexandre M. , Hardwick Steven W. , Alvelos Daniela M. , Mazzon Ricardo R. , Luisi Ben F. , Marques Marilis V. 
Published: April 2017

ABSTRACT

In diverse bacterial lineages, multienzyme assemblies have evolved that are central elements of RNA metabolism and RNA-mediated regulation. The aquatic Gram-negative bacterium
Caulobacter crescentus
, which has been a model system for studying the bacterial cell cycle, has an RNA degradosome assembly that is formed by the endoribonuclease RNase E and includes the DEAD-box RNA helicase RhlB. Immunoprecipitations of extracts from cells expressing an epitope-tagged RNase E reveal that RhlE, another member of the DEAD-box helicase family, associates with the degradosome at temperatures below those optimum for growth. Phenotype analyses of
rhlE
,
rhlB
, and
rhlE rhlB
mutant strains show that RhlE is important for cell fitness at low temperature and its role may not be substituted by RhlB. Transcriptional and translational fusions of
rhlE
to the
lacZ
reporter gene and immunoblot analysis of an epitope-tagged RhlE indicate that its expression is induced upon temperature decrease, mainly through posttranscriptional regulation. RNase E pulldown assays show that other proteins, including the transcription termination factor Rho, a second DEAD-box RNA helicase, and ribosomal protein S1, also associate with the degradosome at low temperature. The results suggest that the RNA degradosome assembly can be remodeled with environmental change to alter its repertoire of helicases and other accessory proteins.

IMPORTANCE
DEAD-box RNA helicases are often present in the RNA degradosome complex, helping unwind secondary structures to facilitate degradation.
Caulobacter crescentus
is an interesting organism to investigate degradosome remodeling with change in temperature, because it thrives in freshwater bodies and withstands low temperature. In this study, we show that at low temperature, the cold-induced DEAD-box RNA helicase RhlE is recruited to the RNA degradosome, along with other helicases and the Rho protein. RhlE is essential for bacterial fitness at low temperature, and its function may not be complemented by RhlB, although RhlE is able to complement for
rhlB
loss. These results suggest that RhlE has a specific role in the degradosome at low temperature, potentially improving adaptation to this condition.
Contradictory coroners? Decision-making in death investigations
Authors: Mclean Maxwell 
Published: April 2017

AimNational coroner data demonstrate differences in the rates at which coroners across England and Wales choose to investigate reported deaths and the frequency by which they record certain conclusions. This study sought to examine how decisions are made by coroners and whether they differed when faced with identical case information.MethodsThree different clinical scenarios were circulated via a web link to all senior coroners. The case information was contained within a ‘Decision Board’ displayed on screen. Each scenario had nine consistent categories of information, such as the cause of death and the medical history. Participants were asked to indicate an inquest conclusion (verdict) using free text and to provide comments. The way in which participants accessed the case information (order, frequency, etc) was recorded by the computer software.Results35 coroners responded. There was little consensus as to conclusion with scenarios 1 and 2 generating four different outcomes and scenario 3 generating an extraordinary eight different conclusions among respondents. Despite coming to widely different conclusions, coroners demonstrated very similar decision-making processes. Conclusions were robustly defended yet proffered alternatives were plentiful. The comments made indicated a difference in the personal attitudes of coroners towards case information.ConclusionsDifferent coroners faced with identical case information arrived at widely different case outcomes ranging from no further investigation to finding numerous alternative verdicts. Disparity appeared to be a product of differing personal attitudes among coroners. National coroner consensus to achieve a shared inference from available evidence is urgently needed.
Scared fitless: Context-dependent response of fear to loss of predators over evolutionary time in Drosophila melanogaster
Authors: Elliott Kyle H. , Norris D. Ryan , Betini Gustavo S. , Dworkin Ian 
Published: April 2017

Fear of predation can disappear rapidly in the absence of predators, as bolder individuals outcompete vigilant individuals for food and mates. To examine the evolution of fear in a seasonal environment, we exposed Drosophila melanogaster to mantid predators during the breeding season and the non-breeding season, and compared these with a control. We compared three Drosophila lineages that were maintained in captivity for (1) ∼45 years without mantid predators, (2) ∼5 years without mantid predators, and (3) ∼5 years with mantid predators (predator-evolved). The presence of a predator during the non-breeding season caused reduced fecundity in the following breeding season, independent of the evolutionary lineage. However, the presence of a predator during reproduction caused offspring to emerge earlier, and this effect was more pronounced in the predator-evolved lineage. Thus, the fear response was related to evolutionary lineage only during the larval life stage, which is when foraging competition, and hence the cost of fear, may be highest. We present one of the first experimental demonstrations that emotion (fear) can evolve in response to environmental context.
An upper bound for the Tarski numbers of nonamenable groups of piecewise projective homeomorphisms
Authors: Lodha Yash 
Published: April 2017

The Tarski number of a nonamenable group is the smallest number of pieces needed for a paradoxical decomposition of the group. Nonamenable groups of piecewise projective homeomorphisms were introduced in [N. Monod, Groups of piecewise projective homeomorphisms, Proc. Natl. Acad. Sci. 110(12) (2013) 4524–4527], and nonamenable finitely presented groups of piecewise projective homeomorphisms were introduced in [Y. Lodha and J. T. Moore, A finitely presented non amenable group of piecewise projective homeomorphisms, Groups, Geom. Dyn. 10(1) (2016) 177–200]. These groups do not contain non-abelian free subgroups. In this paper, we prove that the Tarski number of all groups in both families is at most 25. In particular, we demonstrate the existence of a paradoxical decomposition with 25 pieces. Our argument also applies to any group of piecewise projective homeomorphisms that contains as a subgroup the group of piecewise [Formula: see text] homeomorphisms of [Formula: see text] with rational breakpoints and an affine map that is a not an integer translation.