bluuebunny/crossref_metadata_2025_split huggingface dataset:
Resistance to Colistin Associated with a Single Amino Acid Change in Protein PmrB among Klebsiella pneumoniae Isolates of Worldwide Origin
Authors: Jayol Aurélie , Poirel Laurent , Brink Adrian , Villegas Maria-Virginia , Yilmaz Mesut , Nordmann Patrice 
Published: June 2014

ABSTRACT

A series of colistin-resistant
Klebsiella pneumoniae
isolates recovered from different countries was investigated in order to evaluate the involvement of the PmrA/PmrB two-component system in this resistance. Six isolates possessed a mutated PmrB protein, which is encoded by the
pmrB
gene, part of the
pmrCAB
operon involved in lipopolysaccharide modification. The same amino acid substitution (Thr157Pro) in PmrB was identified in the six isolates. The six isolates belonged to four distinct clonal groups, recovered in South Africa (sequence type 14 [ST14]), Turkey (ST101), and Colombia (ST258 and ST15). Three out of the four clones produced a carbapenemase, OXA-181, OXA-48, or KPC-3, while a single isolate did not produce any carbapenemase. Expression assays revealed an overexpression of the
pmrA
(70-fold),
pmrB
(70-fold),
pmrC
(170-fold), and
pmrK
(40-fold) genes in the
pmrB
-mutated isolate compared to expression of the
pmrB
wild-type isogenic
K. pneumoniae
isolate, confirming that the PmrB substitution was responsible for increased expression levels of those genes. Complementation assays leading to the expression of a wild-type PmrB protein restored the susceptibility to colistin in all isolates, confirming that the substitution in PmrB was responsible for the resistance phenotype. This study identified a key amino acid located in the PmrB protein as being responsible for the overexpression of
pmrCAB
and
pmrHFIJKLM
operons, leading to resistance to colistin.
Treatment of Murine Cerebral Malaria by Artemisone in Combination with Conventional Antimalarial Drugs: Antiplasmodial Effects and Immune Responses
Authors: Guiguemde W. Armand , Hunt Nicholas H. , Guo Jintao , Marciano Annael , Haynes Richard K. , Clark Julie , Guy R. Kiplin , Golenser Jacob 
Published: June 2014

ABSTRACTThe decreasing effectiveness of antimalarial therapy due to drug resistance necessitates constant efforts to develop new drugs. Artemisinin derivatives are the most recent drugs that have been introduced and are considered the first line of treatment, but there are already indications ofPlasmodium falciparumresistance to artemisinins. Consequently, drug combinations are recommended for prevention of the induction of resistance. The research here demonstrates the effects of novel combinations of the new artemisinin derivative, artemisone, a recently described 10-alkylamino artemisinin derivative with improved antimalarial activity and reduced neurotoxicity. We here investigate its ability to killP. falciparumin a high-throughputin vitroassay and to protect mice against lethal cerebral malaria caused byPlasmodium bergheiANKA when used alone or in combination with established antimalarial drugs. Artemisone effects againstP. falciparumin vitrowere synergistic with halofantrine and mefloquine, and additive with 25 other drugs, including chloroquine and doxycycline. The concentrations of artemisone combinations that were toxic against THP-1 cellsin vitrowere much higher than their effective antimalarial concentration. Artemisone, mefloquine, chloroquine, or piperaquine given individually mostly protected mice against cerebral malaria caused byP. bergheiANKA but did not prevent parasite recrudescence. Combinations of artemisone with any of the other three drugs did completely cure most mice of malaria. The combination of artemisone and chloroquine decreased the ratio of proinflammatory (gamma interferon, tumor necrosis factor) to anti-inflammatory (interleukin 10 [IL-10], IL-4) cytokines in the plasma ofP. berghei-infected mice. Thus, artemisone in combinations with other antimalarial drugs might have a dual action, both killing parasites and limiting the potentially deleterious host inflammatory response.
Multidisciplinary Analysis of a Nontoxigenic Clostridium difficile Strain with Stable Resistance to Metronidazole
Authors: Moura Ines , Monot Marc , Tani Chiara , Spigaglia Patrizia , Barbanti Fabrizio , Norais Nathalie , Dupuy Bruno , Bouza Emilio , Mastrantonio Paola 
Published: June 2014

ABSTRACT

Stable resistance to metronidazole in a nontoxigenic
Clostridium difficile
strain was investigated at both the genomic and proteomic levels. Alterations in the metabolic pathway involving the pyruvate-ferredoxin oxidoreductase were found, suggesting that reduction of metronidazole, required for its activity, may be less efficient in this strain. Proteomic studies also showed a cellular response to oxidative stress.
Heterogeneity of Molecular Resistance Patterns in Antimony-Resistant Field Isolates of Leishmania Species from the Western Mediterranean Area
Authors: Jeddi Fakhri , Mary Charles , Aoun Karim , Harrat Zoubir , Bouratbine Aïda , Faraut Françoise , Benikhlef Rezika , Pomares Christelle , Pratlong Francine , Marty Pierre , Piarroux Renaud 
Published: June 2014

ABSTRACT

Antimonials remain the first-line treatment for the various manifestations of leishmaniasis in most areas where the disease is endemic, and increasing cases of therapeutic failure associated with parasite resistance have been reported. In this study, we assessed the molecular status of 47 clinical isolates of
Leishmania
causing visceral and cutaneous leishmaniasis from Algeria, Tunisia, and southern France. In total, we examined 14 genes that have been shown to exhibit significant variations in DNA amplification, mRNA levels, or protein expression with respect to resistance to antimonials. The gene status of each clinical isolate was assessed via qPCR and qRT-PCR. We then compared the molecular pattern against the phenotype determined via an
in vitro
sensitivity test of the clinical isolates against meglumine antimoniate, which is considered the reference technique. Our results demonstrate significant DNA amplification and/or RNA overexpression in 56% of the clinical isolates with the resistant phenotype. All clinical isolates that exhibited significant overexpression of at least 2 genes displayed a resistant phenotype. Among the 14 genes investigated, 10 genes displayed either significant amplification or overexpression in at least 1 clinical isolate; these genes are involved in several metabolic pathways. Moreover, various gene associations were observed depending on the clinical isolates, supporting the multifactorial nature of
Leishmania
resistance. Molecular resistance features were found in the 3
Leishmania
species investigated (
Leishmania infantum
,
Leishmania major
, and
Leishmania killicki
). To our knowledge, this is the first report of the involvement of molecular resistance genes in field isolates of
Leishmania major
and
Leishmania killicki
with the resistance phenotype.
Scalable Preparation and Differential Pharmacologic and Toxicologic Profiles of Primaquine Enantiomers
Authors: Nanayakkara N. P. Dhammika , Tekwani Babu L. , Herath H. M. T. Bandara , Sahu Rajnish , Gettayacamin Montip , Tungtaeng Anchalee , van Gessel Yvonne , Baresel Paul , Wickham Kristina S. , Bartlett Marilyn S. , Fronczek Frank R. , Melendez Victor , Ohrt Colin , Reichard Gregory A. , McChesney James D. , Rochford Rosemary , Walker Larry A. 
Published: June 2014

ABSTRACT

Hematotoxicity in individuals genetically deficient in glucose-6-phosphate dehydrogenase (G6PD) activity is the major limitation of primaquine (PQ), the only antimalarial drug in clinical use for treatment of relapsing
Plasmodium vivax
malaria. PQ is currently clinically used in its racemic form. A scalable procedure was developed to resolve racemic PQ, thus providing pure enantiomers for the first time for detailed preclinical evaluation and potentially for clinical use. These enantiomers were compared for antiparasitic activity using several mouse models and also for general and hematological toxicities in mice and dogs. (+)-(
S
)-PQ showed better suppressive and causal prophylactic activity than (−)-(
R
)-PQ in mice infected with
Plasmodium berghei
. Similarly, (+)-(
S
)-PQ was a more potent suppressive agent than (−)-(
R
)-PQ in a mouse model of
Pneumocystis carinii
pneumonia. However, at higher doses, (+)-(
S
)-PQ also showed more systemic toxicity for mice. In beagle dogs, (+)-(
S
)-PQ caused more methemoglobinemia and was toxic at 5 mg/kg of body weight/day given orally for 3 days, while (−)-(
R
)-PQ was well tolerated. In a novel mouse model of hemolytic anemia associated with human G6PD deficiency, it was also demonstrated that (−)-(
R
)-PQ was less hemolytic than (+)-(
S
)-PQ for the G6PD-deficient human red cells engrafted in the NOD-SCID mice. All these data suggest that while (+)-(
S
)-PQ shows greater potency in terms of antiparasitic efficacy in rodents, it is also more hematotoxic than (−)-(
R
)-PQ in mice and dogs. Activity and toxicity differences of PQ enantiomers in different species can be attributed to their different pharmacokinetic and metabolic profiles. Taken together, these studies suggest that (−)-(
R
)-PQ may have a better safety margin than the racemate in human.
Identification of a Novel Clone, ST736, among Enterococcus faecium Clinical Isolates and Its Association with Daptomycin Nonsusceptibility
Authors: Wang Guiqing , Kamalakaran Sitharthan , Dhand Abhay , Huang Weihua , Ojaimi Caroline , Zhuge Jian , Yee Leslie Lee , Mayigowda Pramod , Surendraiah Pavan Kumar Makam , Dimitrova Nevenka , Fallon John T. 
Published: June 2014

ABSTRACT

Resistance to daptomycin in enterococcal clinical isolates remains rare but is being increasingly reported in the United States and worldwide. There are limited data on the genetic relatedness and microbiological and clinical characteristics of daptomycin-nonsusceptible enterococcal clinical isolates. In this study, we assessed the population genetics of daptomycin-nonsusceptible
Enterococcus faecium
(DNSE) clinical isolates by multilocus sequence typing (MLST) and whole-genome sequencing analysis. Forty-two nonduplicate DNSE isolates and 43 randomly selected daptomycin-susceptible
E. faecium
isolates were included in the analysis. All
E. faecium
isolates were recovered from patients at a tertiary care medical center in suburban New York City from May 2009 through December 2013. The daptomycin MICs of the DNSE isolates ranged from 6 to >256 μg/ml. Three major clones of
E. faecium
(ST18, ST412, and ST736) were identified among these clinical isolates by MLST and whole-genome sequence-based analysis. A newly recognized clone, ST736, was seen in 32 of 42 (76.2%) DNSE isolates and in only 14 of 43 (32.6%) daptomycin-susceptible
E. faecium
isolates (
P
< 0.0001). This report provides evidence of the association between
E. faecium
clone ST736 and daptomycin nonsusceptibility. The identification and potential spread of this novel
E. faecium
clone and its association with daptomycin nonsusceptibility constitute a challenge for patient management and infection control at our medical center.
KAF156 Is an Antimalarial Clinical Candidate with Potential for Use in Prophylaxis, Treatment, and Prevention of Disease Transmission
Authors: Kuhen Kelli L. , Chatterjee Arnab K. , Rottmann Matthias , Gagaring Kerstin , Borboa Rachel , Buenviaje Jennifer , Chen Zhong , Francek Carolyn , Wu Tao , Nagle Advait , Barnes S. Whitney , Plouffe David , Lee Marcus C. S. , Fidock David A. , Graumans Wouter , van de Vegte-Bolmer Marga , van Gemert Geert J. , Wirjanata Grennady , Sebayang Boni , Marfurt Jutta , Russell Bruce , Suwanarusk Rossarin , Price Ric N. , Nosten Francois , Tungtaeng Anchalee , Gettayacamin Montip , Sattabongkot Jetsumon , Taylor Jennifer , Walker John R. , Tully David , Patra Kailash P. , Flannery Erika L. , Vinetz Joseph M. , Renia Laurent , Sauerwein Robert W. , Winzeler Elizabeth A. , Glynne Richard J. , Diagana Thierry T. 
Published: June 2014

ABSTRACT

Renewed global efforts toward malaria eradication have highlighted the need for novel antimalarial agents with activity against multiple stages of the parasite life cycle. We have previously reported the discovery of a novel class of antimalarial compounds in the imidazolopiperazine series that have activity in the prevention and treatment of blood stage infection in a mouse model of malaria. Consistent with the previously reported activity profile of this series, the clinical candidate KAF156 shows blood schizonticidal activity with 50% inhibitory concentrations of 6 to 17.4 nM against
P. falciparum
drug-sensitive and drug-resistant strains, as well as potent therapeutic activity in a mouse models of malaria with 50, 90, and 99% effective doses of 0.6, 0.9, and 1.4 mg/kg, respectively. When administered prophylactically in a sporozoite challenge mouse model, KAF156 is completely protective as a single oral dose of 10 mg/kg. Finally, KAF156 displays potent
Plasmodium
transmission blocking activities both
in vitro
and
in vivo
. Collectively, our data suggest that KAF156, currently under evaluation in clinical trials, has the potential to treat, prevent, and block the transmission of malaria.
Population Pharmacokinetic-Pharmacodynamic Analysis of Voriconazole and Anidulafungin in Adult Patients with Invasive Aspergillosis
Authors: Liu Ping , Mould Diane R. 
Published: June 2014

ABSTRACT

To evaluate the exposure-response relationships for efficacy and safety of voriconazole and anidulafungin in adult patients with invasive aspergillosis (IA), a population pharmacokinetic-pharmacodynamic (PK-PD) analysis was performed with data from a phase 3, prospective, double-blind, comparative study evaluating voriconazole and anidulafungin combination therapy versus voriconazole (and placebo) monotherapy. Anidulafungin/placebo treatment duration was 2 to 4 weeks, and voriconazole treatment duration was 6 weeks. Efficacy (6-week all-causality mortality and 6-week global response [
n
= 176]) and safety (hepatic [
n
= 238], visual [
n
= 199], and psychiatric [
n
= 183] adverse events [AEs]) endpoints were analyzed separately using a binary logistic regression model. In IA patients receiving voriconazole monotherapy, no positive associations between voriconazole exposure and efficacy or safety were identified. In IA patients receiving combination therapy, no positive associations between voriconazole or anidulafungin exposures and efficacy were identified. The 6-week survival rate tended to increase as anidulafungin treatment duration increased; this finding should be considered with caution. Additionally, in IA patients receiving combination therapy, a positive association between voriconazole and anidulafungin exposures (area under the curve [AUC] and trough concentration [
C
min
]) and hepatic AEs was established; a weak positive association between voriconazole exposure (AUC and
C
min
) and psychiatric AEs was also established, but no association between voriconazole exposure and visual AEs was identified. Besides the drug exposures, no other covariates (i.e., CYP2C19 genotype status, age, weight, body mass index, sex, race, or neutropenia status) were identified as significant predictors of the efficacy and safety endpoints in IA patients. This study was registered on
ClinicalTrials.gov
(NCT00531479).
Safety and Pharmacokinetics of XOMA 3AB, a Novel Mixture of Three Monoclonal Antibodies against Botulinum Toxin A
Authors: Nayak S. U. , Griffiss J. M. , McKenzie R. , Fuchs E. J. , Jurao R. A. , An A. T. , Ahene A. , Tomic M. , Hendrix C. W. , Zenilman J. M. 
Published: June 2014

ABSTRACT

Botulinum neurotoxin A is a category A bioterrorism agent. Current antitoxin therapies are scarce and produce adverse reactions. XOMA 3AB consists of 3 IgG1 monoclonal antibodies (MAbs), each with a distinct human or humanized variable region, which bind to distinct epitopes on botulinum neurotoxin serotype A. This first-in-human study evaluated the safety and pharmacokinetics (PK) of escalating doses of XOMA 3AB administered intravenously (i.v.) to healthy adults. In this double-blind placebo-controlled dose escalation study, 3 cohorts of 8 healthy subjects received a single intravenous dose of XOMA 3AB or placebo at a 3:1 ratio. Follow-up examinations included physical examinations, hematology and chemistry blood tests, electrocardiograms, and pharmacokinetics. Pharmacokinetic parameters were estimated using noncompartmental methods. There were no infusion discontinuations or hypersensitivity reactions. Two or more subjects experienced headache, hyperglycemia, or anemia; none was dose related. All adverse events (AEs) were mild to moderate except for an episode of exercise-induced elevation of a subject's creatine phosphokinase (CPK) level, unrelated to XOMA 3AB. Concentration-time plots demonstrated a peak in MAb concentrations 1 to 2 h after completion of the infusion, after which the levels declined in a biexponential decay pattern for all analytes. For each MAb, the maximum concentration of drug in serum (
C
max
) and the area under the concentration-time curve from 0 to infinity (AUC
inf
) increased as the dose increased. Clearance of the humanized mouse MAb was more rapid than that of the two fully human MAbs, particularly at the lowest dose. None of the MAbs was immunogenic. At the doses administered, XOMA 3AB was well tolerated. These safety findings support further investigation of XOMA 3AB as a potential agent for botulism treatment and postexposure prophylaxis. (This study has been registered at ClinicalTrials.gov under registration no. NCT01357213.)
Serratia marcescens ShlA Pore-Forming Toxin Is Responsible for Early Induction of Autophagy in Host Cells and Is Transcriptionally Regulated by RcsB
Authors: Di Venanzio Gisela , Stepanenko Tatiana M. , García Véscovi Eleonora 
Published: June 2014

ABSTRACT

Serratia marcescens
is a Gram-negative bacterium that thrives in a wide variety of ambient niches and interacts with an ample range of hosts. As an opportunistic human pathogen, it has increased its clinical incidence in recent years, being responsible for life-threatening nosocomial infections.
S. marcescens
produces numerous exoproteins with toxic effects, including the ShlA pore-forming toxin, which has been catalogued as its most potent cytotoxin. However, the regulatory mechanisms that govern ShlA expression, as well as its action toward the host, have remained unclear. We have shown that
S. marcescens
elicits an autophagic response in host nonphagocytic cells. In this work, we determine that the expression of ShlA is responsible for the autophagic response that is promoted prior to bacterial internalization in epithelial cells. We show that a strain unable to express ShlA is no longer able to induce this autophagic mechanism, while heterologous expression of ShlA/ShlB suffices to confer on noninvasive
Escherichia coli
the capacity to trigger autophagy. We also demonstrate that
shlBA
harbors a binding motif for the RcsB regulator in its promoter region. RcsB-dependent control of
shlBA
constitutes a feed-forward regulatory mechanism that allows interplay with flagellar-biogenesis regulation. At the top of the circuit, activated RcsB downregulates expression of flagella by binding to the
flhDC
promoter region, preventing FliA-activated transcription of
shlBA
. Simultaneously, RcsB interaction within the
shlBA
promoter represses ShlA expression. This circuit offers multiple access points to fine-tune ShlA production. These findings also strengthen the case for an RcsB role in orchestrating the expression of
Serratia
virulence factors.
Microbiota-Driven Immune Cellular Maturation Is Essential for Antibody-Mediated Adaptive Immunity to Staphylococcus aureus Infection in the Eye
Authors: Zaidi Tanweer , Zaidi Tauqeer , Cywes-Bentley Colette , Lu Roger , Priebe Gregory P. , Pier Gerald B. 
Published: June 2014

ABSTRACT

As an immune-privileged site, the eye, and particularly the outer corneal surface, lacks resident mature immune effector cells. Physical barriers and innate mediators are the best-described effectors of immunity in the cornea. When the barriers are breached, infection can result in rapid tissue destruction, leading to loss of visual acuity and frank blindness. To determine the cellular and molecular components needed for effective adaptive immunity on the corneal surface, we investigated which immune system effectors were required for protection against
Staphylococcus aureus
corneal infections in mice, which are a serious cause of human eye infections. Both systemically injected and topically applied antibodies to the conserved cell surface polysaccharide poly-
N
-acetylglucosamine (PNAG) were effective at mediating reductions in corneal pathology and bacterial levels. Additional host factors impacting protection included intercellular adhesion molecule 1 (ICAM-1)-dependent polymorphonuclear leukocyte (PMN) recruitment, functional CD4
+
T cells, signaling via the interleukin-17 (IL-17) receptor, and IL-22 production. In germfree mice, there was no protective efficacy of antibody to PNAG due to the lack of LY6G
+
inflammatory cell coeffector recruitment to the cornea. Protection was manifest after 3 weeks of exposure to conventional mice and acquisition of a resident microbiota. We conclude that in the anterior eye, ICAM-1-mediated PMN recruitment to the infected cornea along with endogenous microbiota-matured CD4
+
T cells producing both IL-17 and IL-22 is required for antibody to PNAG to protect against
S. aureus
infection.
Leucine-Responsive Regulatory Protein Lrp and PapI Homologues Influence Phase Variation of CS31A Fimbriae
Authors: Graveline Richard , Garneau Philippe , Martin Christine , Mourez Michaël , Hancock Mark A. , Lavoie Rémi , Harel Josée 
Published: June 2014

ABSTRACTCS31A, a K88-related surface antigen specified by theclpoperon, is a member of the type P family of adhesive factors and plays a key role in the establishment of disease caused by septicemic and enterotoxigenicEscherichia colistrains. Its expression is under the control of methylation-dependent transcriptional regulation, for which the leucine-responsive regulatory protein (Lrp) is essential. CS31A is preferentially in the OFF state and exhibits distinct regulatory features compared to the regulation of other P family members. In the present study, surface plasmon resonance and DNase I protection assays showed that Lrp binds to the distal moiety of theclpregulatory region with low micromolar affinity compared to its binding to the proximal moiety, which exhibits stronger, nanomolar affinity. The complex formation was also influenced by the addition of PapI or FooI, which increased the affinity of Lrp for theclpdistal and proximal regions and was required to induce phase variation. The influence of PapI or FooI, however, was predominantly associated with a more complete shutdown ofclpexpression, in contrast to what has previously been observed with AfaF (a PapI ortholog). Taken together, these results suggest that the preferential OFF state observed in CS31A cells is mainly due to the weak interaction of the leucine-responsive regulatory protein with theclpdistal region and that the PapI homolog favors the OFF phase. Within the large repertoire of fimbrial variants in the P family, our study illustrates that having a fimbrial operon that lacks its own PapI ortholog allows it to be more flexibly regulated by other orthologs in the cell.