bluuebunny/crossref_metadata_2025_split huggingface dataset:
Luciferase-Based, High-Throughput Assay for Screening and Profiling Transmission-Blocking Compounds against Plasmodium falciparum Gametocytes
Authors: Lucantoni Leonardo , Fidock David A. , Avery Vicky M. 
Published: January 2016

ABSTRACT

The discovery of new antimalarial drugs able to target both the asexual and gametocyte stages of
Plasmodium falciparum
is critical to the success of the malaria eradication campaign. We have developed and validated a robust, rapid, and cost-effective high-throughput reporter gene assay to identify compounds active against late-stage (stage IV and V) gametocytes. The assay, which is suitable for testing compound activity at incubation times up to 72 h, demonstrates excellent quality and reproducibility, with average
Z
′ values of 0.85 ± 0.01. We used the assay to screen more than 10,000 compounds from three chemically diverse libraries. The screening outcomes highlighted the opportunity to use collections of compounds with known activity against the asexual stages of the parasites as a starting point for gametocytocidal activity detection in order to maximize the chances of identifying gametocytocidal compounds. This assay extends the capabilities of our previously reported luciferase assay, which tested compounds against early-stage gametocytes, and opens possibilities to profile the activities of gametocytocidal compounds over the entire course of gametocytogenesis.
The Nonartemisinin Sesquiterpene Lactones Parthenin and Parthenolide Block Plasmodium falciparum Sexual Stage Transmission
Authors: Balaich Jared N. , Mathias Derrick K. , Torto Baldwyn , Jackson Bryan T. , Tao Dingyin , Ebrahimi Babak , Tarimo Brian B. , Cheseto Xavier , Foster Woodbridge A. , Dinglasan Rhoel R. 
Published: January 2016

ABSTRACTParthenin and parthenolide are natural products that are closely related in structure to artemisinin, which is also a sesquiterpene lactone (SQL) and one of the most important antimalarial drugs available. Parthenin, like artemisinin, has an effect onPlasmodiumblood stage development. We extended the evaluation of parthenin as a potential therapeutic for the transmissible stages ofPlasmodium falciparumas it transitions between human and mosquito, with the aim of gaining potential mechanistic insight into the inhibitory activity of this compound. We posited that if parthenin targets different biological pathways in the parasite, this in turn could pave the way for the development of druggable compounds that could prevent the spread of artemisinin-resistant parasites. We examined parthenin's effect on male gamete activation and the ookinete-to-oocyst transition in the mosquito as well as on stage V gametocytes that are present in peripheral blood. Parthenin arrested parasite development for each of the stages tested. The broad inhibitory properties of parthenin on the evaluated parasite stages may suggest different mechanisms of action between parthenin and artemisinin. Parthenin's cytotoxicity notwithstanding, its demonstrated activity in this study suggests that structurally related SQLs with a better safety profile deserve further exploration. We used our battery of assays to test parthenolide, which has a more compelling safety profile. Parthenolide demonstrated activity nearly identical to that of parthenin againstP. falciparum, highlighting its potential as a possible transmission-blocking drug scaffold. We discuss the context of the evidence with respect to the next steps toward expanding the current antimalarial arsenal.
Clinical Utility and Safety of a Model-Based Patient-Tailored Dose of Vancomycin in Neonates
Authors: Leroux Stéphanie , Jacqz-Aigrain Evelyne , Biran Valérie , Lopez Emmanuel , Madeleneau Doriane , Wallon Camille , Zana-Taïeb Elodie , Virlouvet Anne-Laure , Rioualen Stéphane , Zhao Wei 
Published: January 2016

ABSTRACT
Pharmacokinetic modeling has often been applied to evaluate vancomycin pharmacokinetics in neonates. However, clinical application of the model-based personalized vancomycin therapy is still limited. The objective of the present study was to evaluate the clinical utility and safety of a model-based patient-tailored dose of vancomycin in neonates. A model-based vancomycin dosing calculator, developed from a population pharmacokinetic study, has been integrated into the routine clinical care in 3 neonatal intensive care units (Robert Debré, Cochin Port Royal, and Clocheville hospitals) between 2012 and 2014. The target attainment rate, defined as the percentage of patients with a first therapeutic drug monitoring serum vancomycin concentration achieving the target window of 15 to 25 mg/liter, was selected as an endpoint for evaluating the clinical utility. The safety evaluation was focused on nephrotoxicity. The clinical application of the model-based patient-tailored dose of vancomycin has been demonstrated in 190 neonates. The mean (standard deviation) gestational and postnatal ages of the study population were 31.1 (4.9) weeks and 16.7 (21.7) days, respectively. The target attainment rate increased from 41% to 72% without any case of vancomycin-related nephrotoxicity. This proof-of-concept study provides evidence for integrating model-based antimicrobial therapy in neonatal routine care.
Selective Conditions for a Multidrug Resistance Plasmid Depend on the Sociality of Antibiotic Resistance
Authors: Bottery Michael J. , Wood A. Jamie , Brockhurst Michael A. 
Published: January 2016

ABSTRACT

Multidrug resistance (MDR) plasmids frequently carry antibiotic resistance genes conferring qualitatively different mechanisms of resistance. We show here that the antibiotic concentrations selecting for the RK2 plasmid in
Escherichia coli
depend upon the sociality of the drug resistance: the selection for selfish drug resistance (efflux pump) occurred at very low drug concentrations, just 1.3% of the MIC of the plasmid-free antibiotic-sensitive strain, whereas selection for cooperative drug resistance (modifying enzyme) occurred at drug concentrations exceeding the MIC of the plasmid-free strain.
The Hemagglutinin Stem-Binding Monoclonal Antibody VIS410 Controls Influenza Virus-Induced Acute Respiratory Distress Syndrome
Authors: Baranovich Tatiana , Jones Jeremy C. , Russier Marion , Vogel Peter , Szretter Kristy J. , Sloan Susan E. , Seiler Patrick , Trevejo Jose M. , Webby Richard J. , Govorkova Elena A. 
Published: January 2016

ABSTRACT
Most cases of severe influenza are associated with pulmonary complications, such as acute respiratory distress syndrome (ARDS), and no antiviral drugs of proven value for treating such complications are currently available. The use of monoclonal antibodies targeting the stem of the influenza virus surface hemagglutinin (HA) is a rapidly developing strategy for the control of viruses of multiple HA subtypes. However, the mechanisms of action of these antibodies are not fully understood, and their ability to mitigate severe complications of influenza has been poorly studied. We evaluated the effect of treatment with VIS410, a human monoclonal antibody targeting the HA stem region, on the development of ARDS in BALB/c mice after infection with influenza A(H7N9) viruses. Prophylactic administration of VIS410 resulted in the complete protection of mice against lethal A(H7N9) virus challenge. A single therapeutic dose of VIS410 given 24 h after virus inoculation resulted in dose-dependent protection of up to 100% of mice inoculated with neuraminidase inhibitor-susceptible or -resistant A(H7N9) viruses. Compared to the outcomes in mock-treated controls, a single administration of VIS410 improved viral clearance from the lungs, reduced virus spread in lungs in a dose-dependent manner, resulting in a lower lung injury score, reduced the extent of the alteration in lung vascular permeability and protein accumulation in bronchoalveolar lavage fluid, and improved lung physiologic function. Thus, antibodies targeting the HA stem can reduce the severity of ARDS and show promise as agents for controlling pulmonary complications in influenza.
Activity of Bisnaphthalimidopropyl Derivatives against Trypanosoma brucei
Authors: Graça Nuno A. G. , Gaspar Luis , Costa David M. , Loureiro Inês , Thoo-Lin Paul Kong , Ramos Isbaal , Roura Meritxell , Pruvost Alain , Pemberton Ian K. , Loukil Hadjer , MacDougall Jane , Tavares Joana , Cordeiro-da-Silva Anabela 
Published: January 2016

ABSTRACT

Current treatments for African trypanosomiasis are either toxic, costly, difficult to administer, or prone to elicit resistance. This study evaluated the activity of bisnaphthalimidopropyl (BNIP) derivatives against
Trypanosoma brucei
. BNIPDiaminobutane (BNIPDabut), the most active of these compounds, showed
in vitro
inhibition in the single-unit nanomolar range, similar to the activity in the reference drug pentamidine, and presented low toxicity and adequate metabolic stability. Additionally, using a murine model of acute infection and live imaging, a significant decrease in parasite load in BNIPDabut-treated mice was observed. However, cure was not achieved. BNIPDabut constitutes a new scaffold for antitrypanosomal drugs that deserves further consideration.
Impact of Surotomycin on the Gut Microbiota of Healthy Volunteers in a Phase 1 Clinical Trial
Authors: Citron Diane M. , Tyrrell Kerin L. , Dale Suzanne E. , Chesnel Laurent , Goldstein Ellie J. C. 
Published: January 2016

ABSTRACT

Clostridium difficile
-associated diarrhea has been associated with disruption of the normal intestinal microbiota, particularly the
Bacteroides fragilis
group and
Prevotella
species. Surotomycin is a bactericidal cyclic lipopeptide in development for treatment of
Clostridium difficile
-associated diarrhea that has selective and potent activity against
C. difficile
and other Gram-positive bacteria and a minimal impact on intestinal Gram-negative organisms. The impacts of ascending doses of surotomycin on major organism groups in the gut microbiota of healthy volunteers were evaluated during a randomized, double-blind, placebo-controlled, multiple-dose phase 1 study. Thirty volunteers were randomized into 3 cohorts, using a 4:1 ratio, to receive 250 mg, 500 mg, or 1,000 mg of surotomycin, or placebo, twice daily for 14 days. Stool samples collected at baseline (days 0 and 1) and at the end of treatment (days 13 to 15) were cultured quantitatively. The
B. fragilis
group, the
Bacteroides
/
Prevotella
group, and
Enterobacteriaceae
were also quantified by quantitative real-time PCR. Baseline and end-of-treatment stool samples showed 1- to 2-log
10
CFU/g reductions in total bacterial counts for most volunteers. Various decreases in clostridial,
Lactobacillus-Bifidobacterium
group, and enterococcus-streptococcus group counts occurred while patients were receiving surotomycin, whereas the enterobacteria and the
B. fragilis
group persisted at the end of treatment. There was no change in enterococcus MICs of surotomycin, nor was vancomycin-resistant
Enterococcus
detected after exposure. Surotomycin at doses of up to 1,000 mg twice daily had only modest disruptive effects on the gut microbiota. The potential sparing of the gut microbiota by surotomycin may decrease the risk of disease recurrence.
Synthetic α-Hydroxytropolones Inhibit Replication of Wild-Type and Acyclovir-Resistant Herpes Simplex Viruses
Authors: Ireland Peter J. , Tavis John E. , D'Erasmo Michael P. , Hirsch Danielle R. , Murelli Ryan P. , Cadiz Mark M. , Patel Bindi S. , Gupta Ankit K. , Edwards Tiffany C. , Korom Maria , Moran Eileen A. , Morrison Lynda A. 
Published: January 2016

ABSTRACT

Herpes simplex virus 1 (HSV-1) and HSV-2 remain major human pathogens despite the development of anti-HSV therapeutics as some of the first antiviral drugs. Current therapies are incompletely effective and frequently drive the evolution of drug-resistant mutants. We recently determined that certain natural troponoid compounds such as β-thujaplicinol readily suppress HSV-1 and HSV-2 replication. Here, we screened 26 synthetic α-hydroxytropolones with the goals of determining a preliminary structure-activity relationship for the α-hydroxytropolone pharmacophore and providing a starting point for future optimization studies. Twenty-five compounds inhibited HSV-1 and HSV-2 replication at 50 μM, and 10 compounds inhibited HSV-1 and HSV-2 at 5 μM, with similar inhibition patterns and potencies against both viruses being observed. The two most powerful inhibitors shared a common biphenyl side chain, were capable of inhibiting HSV-1 and HSV-2 with a 50% effective concentration (EC
50
) of 81 to 210 nM, and also strongly inhibited acyclovir-resistant mutants. Moderate to low cytotoxicity was observed for all compounds (50% cytotoxic concentration [CC
50
] of 50 to >100 μM). Therapeutic indexes ranged from >170 to >1,200. These data indicate that troponoids and specifically α-hydroxytropolones are a promising lead scaffold for development as anti-HSV drugs provided that toxicity can be further minimized. Troponoid drugs are envisioned to be employed alone or in combination with existing nucleos(t)ide analogs to suppress HSV replication far enough to prevent viral shedding and to limit the development of or treat nucleos(t)ide analog-resistant mutants.
Pharmacokinetics-Pharmacodynamics of Tazobactam in Combination with Piperacillin in an
In Vitro
Infection Model
Authors: Nicasio Anthony M. , VanScoy Brian D. , Mendes Rodrigo E. , Castanheira Mariana , Bulik Catharine C. , Okusanya Olanrewaju O. , Bhavnani Sujata M. , Forrest Alan , Jones Ronald N. , Friedrich Lawrence V. , Steenbergen Judith N. , Ambrose Paul G. 
Published: January 2016

ABSTRACT

We have previously demonstrated the pharmacokinetic-pharmacodynamic (PK-PD) index best associated with the efficacy of tazobactam when used in combination with ceftolozane to be the percentage of the dosing interval during which tazobactam concentrations remained above a threshold value (%time>threshold). Using an
in vitro
infection model and the same isogenic CTX-M-15-producing
Escherichia coli
triplet set genetically engineered to transcribe different levels of
bla
CTX-M-15
, herein we describe dose fractionation studies designed to evaluate the PK-PD index associated with tazobactam efficacy, when given in combination with piperacillin, and the impact of the presence of a different β-lactam agent, or different
bla
CTX-M-15
transcription levels, on the magnitude of the tazobactam PK-PD index necessary for efficacy. The recombinant strains demonstrated piperacillin MIC values of 128, >256, and >256 μg/ml for the low-, moderate-, and high-level CTX-M-15-producing
E. coli
strains, respectively. The MIC value for piperacillin in the presence of 4 μg/ml of tazobactam was 2 μg/ml for all three strains. The PK-PD index associated with tazobactam efficacy was confirmed to be %time>threshold, regardless of β-lactamase transcription (
r
2
= 0.839). The tazobactam concentration thresholds, however, changed with the CTX-M-15 transcription level and were 0.25, 0.5, and 2 μg/ml for the low-, moderate-, and high-level CTX-M-15-producing strains, respectively (
r
2
= 0.921, 0.773, and 0.875, respectively). The %time>threshold values for tazobactam necessary for net bacterial stasis and a 1- and 2-log
10
-unit CFU/ml decrease from baseline at 24 h were 44.9, 62.9, and 84.9%, respectively. In addition to verifying our previous study results, these results also demonstrated that the magnitude of bacterial-cell killing associated with a β-lactam–β-lactamase inhibitor combination is dependent on the amount of β-lactamase produced. These data provide important information for the development of β-lactam–β-lactamase inhibitor combination agents.
Genomic Characterization of Enterobacter cloacae Isolates from China That Coproduce KPC-3 and NDM-1 Carbapenemases
Authors: Du Hong , Chen Liang , Chavda Kalyan D. , Pandey Ruchi , Zhang Haifang , Xie Xiaofang , Tang Yi-Wei , Kreiswirth Barry N. 
Published: January 2016

ABSTRACT

Here, we report two
Enterobacter cloacae
sequence type 231 isolates coproducing KPC-3 and NDM-1 that have caused lethal infections in a tertiary hospital in China. The
bla
NDM-1
-harboring plasmids carry IncA/C
2
and IncR replicons, showing a mosaic plasmid structure, and the
bla
NDM-1
is harbored on a novel class I integron-like element.
bla
KPC-3
is located on a Tn
3
-Δ
bla
TEM-1
-
bla
KPC-3
-ΔTn
1722
element, flanked by two 9-bp direct-repeat sequences and harbored on an IncX6 plasmid.
Targets and Mechanisms Associated with Protection from Severe Plasmodium falciparum Malaria in Kenyan Children
Authors: Murungi Linda M. , Sondén Klara , Llewellyn David , Rono Josea , Guleid Fatuma , Williams Andrew R. , Ogada Edna , Thairu Amos , Färnert Anna , Marsh Kevin , Draper Simon J. , Osier Faith H. A. 
Published: January 2016

ABSTRACT

Severe malaria (SM) is a life-threatening complication of infection with
Plasmodium falciparum
. Epidemiological observations have long indicated that immunity against SM is acquired relatively rapidly, but prospective studies to investigate its immunological basis are logistically challenging and have rarely been undertaken. We investigated the merozoite targets and antibody-mediated mechanisms associated with protection against SM in Kenyan children aged 0 to 2 years. We designed a unique prospective matched case-control study of well-characterized SM clinical phenotypes nested within a longitudinal birth cohort of children (
n
= 5,949) monitored over the first 2 years of life. We quantified immunological parameters in sera collected before the SM event in cases and their individually matched controls to evaluate the prospective odds of developing SM in the first 2 years of life. Anti-AMA1 antibodies were associated with a significant reduction in the odds of developing SM (odds ratio [OR] = 0.37; 95% confidence interval [CI] = 0.15 to 0.90;
P
= 0.029) after adjustment for responses to all other merozoite antigens tested, while those against MSP-2, MSP-3,
Plasmodium falciparum
Rh2 [
Pf
Rh2], MSP-1
19
, and the infected red blood cell surface antigens were not. The combined ability of total IgG to inhibit parasite growth and mediate the release of reactive oxygen species from neutrophils was associated with a marked reduction in the odds of developing SM (OR = 0.07; 95% CI = 0.006 to 0.82;
P
= 0.03). Assays of these two functional mechanisms were poorly correlated (Spearman rank correlation coefficient [

r
s

] = 0.12;
P
= 0.07). Our data provide epidemiological evidence that multiple antibody-dependent mechanisms contribute to protective immunity via distinct targets whose identification could accelerate the development of vaccines to protect against SM.
Biological Activities of Uric Acid in Infection Due to Enteropathogenic and Shiga-Toxigenic Escherichia coli
Authors: Crane John K. , Broome Jacqueline E. , Lis Agnieszka 
Published: January 2016

ABSTRACT

In previous work, we identified xanthine oxidase (XO) as an important enzyme in the interaction between the host and enteropathogenic
Escherichia coli
(EPEC) and Shiga-toxigenic
E. coli
(STEC). Many of the biological effects of XO were due to the hydrogen peroxide produced by the enzyme. We wondered, however, if uric acid generated by XO also had biological effects in the gastrointestinal tract. Uric acid triggered inflammatory responses in the gut, including increased submucosal edema and release of extracellular DNA from host cells. While uric acid alone was unable to trigger a chloride secretory response in intestinal monolayers, it did potentiate the secretory response to cyclic AMP agonists. Uric acid crystals were formed
in vivo
in the lumen of the gut in response to EPEC and STEC infections. While trying to visualize uric acid crystals formed during EPEC and STEC infections, we noticed that uric acid crystals became enmeshed in the neutrophilic extracellular traps (NETs) produced from host cells in response to bacteria in cultured cell systems and in the intestine
in vivo
. Uric acid levels in the gut lumen increased in response to exogenous DNA, and these increases were enhanced by the actions of DNase I. Interestingly, addition of DNase I reduced the numbers of EPEC bacteria recovered after a 20-h infection and protected against EPEC-induced histologic damage.
Primary Role for Toll-Like Receptor-Driven Tumor Necrosis Factor Rather than Cytosolic Immune Detection in Restricting Coxiella burnetii Phase II Replication within Mouse Macrophages
Authors: Bradley William P. , Boyer Mark A. , Nguyen Hieu T. , Birdwell L. Dillon , Yu Janet , Ribeiro Juliana M. , Weiss Susan R. , Zamboni Dario S. , Roy Craig R. , Shin Sunny 
Published: January 2016

ABSTRACTCoxiella burnetiireplicates within permissive host cells by employing a Dot/Icm type IV secretion system (T4SS) to translocate effector proteins that direct the formation of a parasitophorous vacuole. C57BL/6 mouse macrophages restrict the intracellular replication of theC. burnetiiNine Mile phase II (NMII) strain. However, eliminating Toll-like receptor 2 (TLR2) permits bacterial replication, indicating that the restriction of bacterial replication is immune mediated. Here, we examined whether additional innate immune pathways are employed by C57BL/6 macrophages to sense and restrict NMII replication. In addition to the known role of TLR2 in detecting and restricting NMII infection, we found that TLR4 also contributes to cytokine responses but is not required to restrict bacterial replication. Furthermore, the TLR signaling adaptors MyD88 and Trif are required for cytokine responses and restricting bacterial replication. TheC. burnetiiNMII T4SS translocates bacterial products into C57BL/6 macrophages. However, there was little evidence of cytosolic immune sensing of NMII, as there was a lack of inflammasome activation, T4SS-dependent cytokine responses, and robust type I interferon (IFN) production, and these pathways were not required to restrict bacterial replication. Instead, endogenous tumor necrosis factor (TNF) produced upon TLR sensing ofC. burnetiiNMII was required to control bacterial replication. Therefore, our findings indicate a primary role for TNF produced upon immune detection ofC. burnetiiNMII by TLRs, rather than cytosolic PRRs, in enabling C57BL/6 macrophages to restrict bacterial replication.
ROSET Model of TonB Action in Gram-Negative Bacterial Iron Acquisition
Authors: Klebba Phillip E. 
Published: January 2016

ABSTRACTTherotationalsurveillance andenergytransfer (ROSET) model of TonB action suggests a mechanism by which the electrochemical proton gradient across the Gram-negative bacterial inner membrane (IM) promotes the transport of iron through ligand-gated porins (LGP) in the outer membrane (OM). TonB associates with the IM by an N-terminal hydrophobic helix that forms a complex with ExbBD. It also contains a central extended length of rigid polypeptide that spans the periplasm and a dimericC-terminal-ββαβ-domain (CTD) with LysM motifs that binds the peptidoglycan (PG) layer beneath the OM bilayer. The TonB CTD forms a dimer with affinity for both PG- and TonB-independent OM proteins (e.g., OmpA), localizing it near the periplasmic interface of the OM bilayer. Porins and other OM proteins associate with PG, and this general affinity allows the TonB CTD dimer to survey the periplasmic surface of the OM bilayer. Energized rotational motion of the TonB N terminus in the fluid IM bilayer promotes the lateral movement of the TonB-ExbBD complex in the IM and of the TonB CTD dimer across the inner surface of the OM. When it encounters an accessible TonB box of a (ligand-bound) LGP, the monomeric form of the CTD binds and recruits it into a 4-stranded β-sheet. Because the CTD is rotating, this binding reaction transfers kinetic energy, created by the electrochemical proton gradient across the IM, through the periplasm to the OM protein. The equilibration of the TonB C terminus between the dimeric and monomeric forms that engage in different binding reactions allows the identification of iron-loaded LGP and then the internalization of iron through their trans-outer membrane β-barrels. Hence, the ROSET model postulates a mechanism for the transfer of energy from the IM to the OM, triggering iron uptake.