bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetic-Pharmacodynamic Assessment of Faropenem in a Lethal Murine
Bacillus anthracis
Inhalation Postexposure Prophylaxis Model
Authors: Gill Stanley C. , Rubino Christopher M. , Bassett Jennifer , Miller Lynda , Ambrose Paul G. , Bhavnani Sujata M. , Beaudry Amber , Li Jinfang , Stone Kimberly Clawson , Critchley Ian , Janjic Nebojsa , Heine Henry S. 
Published: February 2010

ABSTRACT

There are few options for prophylaxis after exposure to
Bacillus anthracis
, especially in children and women of childbearing potential. Faropenem is a β-lactam in the penem subclass that is being developed as an oral prodrug, faropenem medoxomil, for the treatment of respiratory tract infections. Faropenem was shown to have
in vitro
activity against
B. anthracis
strains that variably express the
bla1
β-lactamase (MIC range, ≤0.06 to 1 μg/ml). In this study we evaluated the pharmacokinetic-pharmacodynamic (PK-PD) relationships between the plasma faropenem free-drug (
f
) concentrations and efficacy against
B. anthracis
in a murine postexposure prophylaxis inhalation model. The plasma PKs and PKs-PDs of faropenem were evaluated in BALB/c mice following the intraperitoneal (i.p.) administration of doses ranging from 2.5 to 160 mg/kg of body weight. For the evaluation of efficacy, mice received by inhalation aerosol doses of
B. anthracis
(Ames strain; faropenem MIC, 0.06 μg/ml) at 100 times the 50% lethal dose. The faropenem dosing regimens (10, 20, 40, and 80 mg/kg/day) were administered i.p. at 24 h postchallenge at 4-, 6-, and 12-h intervals for 14 days. The sigmoid maximum-threshold-of-efficacy (
E
max
) model fit the survival data, in which the free-drug area under the concentration-time curve (
f
AUC)/MIC ratio, the maximum concentration of free drug in plasma (
fC
max
)/MIC ratio, and the cumulative percentage of a 24-h period that the free-drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (
f
%
T
MIC
) were each evaluated. Assessment of
f
%
T
MIC
demonstrated the strongest correlation with survival (
R
2
= 0.967) compared to the correlations achieved by assessment of
f
AUC/MIC or
fC
max
/MIC, for which minimal correlations were observed. The 50% effective dose (ED
50
), ED
90
, and ED
99
corresponded to
f
%
T
MIC
values of 10.6, 13.4, and 16.4%, respectively, and
E
max
was 89.3%. Overall, faropenem demonstrated a high level of activity against
B. anthracis
in the murine postexposure prophylaxis inhalation model.
Changes in the Proteome of
Candida albicans
in Response to Azole, Polyene, and Echinocandin Antifungal Agents
Authors: Hoehamer Christopher F. , Cummings Edwin D. , Hilliard George M. , Rogers P. David 
Published: February 2010

ABSTRACT

The yeast
Candida albicans
is an opportunistic human fungal pathogen and the cause of superficial and systemic infections in immunocompromised patients. The classes of antifungal agents most commonly used to treat
Candida
infections are the azoles, polyenes, and echinocandins. In the present study, we identified changes in
C. albicans
protein abundance using two-dimensional polyacrylamide gel electrophoresis and matrix-assisted laser desorption ionization-time of flight mass spectroscopy following exposure to representatives of the azole (ketoconazole), polyene (amphotericin B), and echinocandin (caspofungin) antifungals in an effort to elucidate the adaptive responses to these classes of antifungal agents. We identified 39 proteins whose abundance changed in response to ketoconazole exposure. Some of these proteins are involved in ergosterol biosynthesis and are associated with azole resistance. Exposure to amphotericin B altered the abundance of 43 proteins, including those associated with oxidative stress and osmotic tolerance. We identified 50 proteins whose abundance changed after exposure to caspofungin, including enzymes involved in cell wall biosynthesis and integrity, as well as the regulator of β-1,3-glucan synthase activity, Rho1p. Exposure to caspofungin also increased the abundance of the proteins involved in oxidative and osmotic stress. The common adaptive responses shared by all three antifungal agents included proteins involved in carbohydrate metabolism. Some of these antifungal-responsive proteins may represent potential targets for the development of novel therapeutics that could enhance the antifungal activities of these drugs.
Novel
FKS
Mutations Associated with Echinocandin Resistance in
Candida
Species
Authors: Garcia-Effron Guillermo , Chua Daniel Joseph , Tomada Jon Rupert , DiPersio Joseph , Perlin David S. , Ghannoum Mahmoud , Bonilla Hector 
Published: February 2010

ABSTRACT

We studied three clinical isolates of
Candida
spp. (one
C. tropicalis
isolate and two
C. glabrata
isolates) from patients with invasive candidiasis. The first isolate emerged during echinocandin treatment, while the others emerged after the same treatment. These strains harbored an amino acid substitution in Fksp never linked before with reduced echinocandin susceptibility in
C. tropicalis
or in
C. glabrata
. The molecular mechanism of reduced susceptibility was confirmed using a 1,3-β-
d
-glucan synthase inhibition assay.
Dinitroaniline Activity inToxoplasma gondiiExpressing Wild-Type or Mutant α-Tubulin
Authors: Ma Christopher , Tran Johnson , Gu Frank , Ochoa Roxanna , Li Catherine , Sept David , Werbovetz Karl , Morrissette Naomi 
Published: February 2010

ABSTRACTThe human parasiteToxoplasma gondiiis sensitive to dinitroaniline compounds which selectively disrupt microtubules in diverse protozoa but which have no detectable effect on vertebrate host cell microtubules or other functions. Replication of wild-typeT. gondiiis inhibited by 0.5 to 2.5 μM oryzalin, but mutant parasites harboring amino acid substitutions in the predicted dinitroaniline binding site confer resistance up to 40 μM oryzalin. However, the precise interaction between dinitroanilines and the binding site in α-tubulin remains unclear. We have investigated the activity of 12 dinitroanilines and the related compound amiprophos methyl on wild-type and dinitroaniline-resistant parasite lines that contain proposed binding site mutations. These data indicate that dinitramine is the most effective dinitroaniline to inhibitToxoplasmagrowth in wild-type parasites and most resistant lines. Dinitramine has an amine group at themetaposition not present in any of the other dinitroanilines tested here that is predicted to form hydrogen bonds with residues Arg2 and Gln133 according to docking data. Remarkably, although the binding site mutation Ile235Val confers increased resistance to most dinitroanilines, it confers increased sensitivity to GB-II-5, a compound optimized for activity against kinetoplastid tubulin. Kinetoplastid parasites have a valine at position 235 of α-tubulin, whereas apicomplexan parasites have an isoleucine at this site. We suggest that this heterogeneity in binding site environment influences relative dinitroaniline sensitivity in distinct protozoan lineages and hypothesize that a mutation that makes the apicomplexan dinitroaniline binding site more like the kinetoplastid site increases sensitivity to a dinitroaniline optimized for activity in the latter parasites.
Antistaphylococcal Activity of ACHN-490 Tested Alone and in Combination with Other Agents by Time-Kill Assay
Authors: Lin Gengrong , Ednie Lois M. , Appelbaum Peter C. 
Published: February 2010

ABSTRACT

Synergy time-kill studies of 47 methicillin-resistant
Staphylococcus aureus
strains with differing resistance phenotypes showed that combinations of subinhibitory concentrations of ACHN-490 and daptomycin yielded synergy against 43/47 strains at 24 h, while the combination was indifferent against the remaining 4 strains. ACHN-490 and ceftobiprole showed synergy in 17/47 strains tested at 24 h, while 6/47 strains showed synergy for subinhibitory combinations of ACHN-490 and linezolid.
Fluoroquinolone Resistance in
Streptococcus dysgalactiae
subsp.
equisimilis
and Evidence for a Shared Global Gene Pool with
Streptococcus pyogenes
Authors: Pinho M. D. , Melo-Cristino J. , Ramirez M. 
Published: February 2010

ABSTRACT

Quinolone resistance is an emerging problem in
Streptococcus pyogenes
, and recombination with
Streptococcus dysgalactiae
DNA has been implicated as a frequent mechanism leading to resistance. We have characterized a collection of
S. dysgalactiae
subsp.
equisimilis
isolates responsible for infections in humans (
n
= 314) and found a high proportion of levofloxacin-resistant isolates (12%). Resistance was associated with multiple
emm
types and genetic lineages, as determined by pulsed-field gel electrophoretic profiling. Since we could not find evidence for a role of efflux pumps in resistance, we sequenced the quinolone resistance-determining regions of the
gyrA
and
parC
genes of representative resistant and susceptible isolates. We found much greater diversity among the
parC
genes (19 alleles) than among the
gyrA
genes (5 alleles). While single mutations in either GyrA or ParC were sufficient to raise the MIC so that the strains were classified as intermediately resistant, higher-level resistance was associated with mutations in both GyrA and ParC. Evidence for recombination with
S. pyogenes
DNA was found in some
parC
alleles, but this was not exclusively associated with resistance. Our data support the existence of a common reservoir of genes conferring quinolone resistance shared between
S. dysgalactiae
subsp.
equisimilis
and
S. pyogenes
, while no recombination with the animal pathogen
S. dysgalactiae
subsp.
dysgalactiae
could be found.
Mutant APH(2″)-IIa Enzymes with Increased Activity against Amikacin and Isepamicin
Authors: Toth Marta , Frase Hilary , Chow Joseph W. , Smith Clyde , Vakulenko Sergei B. 
Published: February 2010

ABSTRACT

Directed evolution by random PCR mutagenesis of the gene for the aminoglycoside 2″-IIa phosphotransferase generated R92H/D268N and N196D/D268N mutant enzymes, resulting in elevated levels of resistance to amikacin and isepamicin but not to other aminoglycoside antibiotics. Increases in the activities of the mutant phosphotransferases for isepamicin are the result of decreases in

K
m

values, while improved catalytic efficiency for amikacin is the result of both a decrease in

K
m

values and an increase in turnover of the antibiotic. Enzymes with R92H, D268N, and D268N single amino acid substitutions did not result in elevated MICs for aminoglycosides.
Correlation between
In
Vitro
Activity of Posaconazole and
In
Vivo
Efficacy against
Rhizopus oryzae
Infection in Mice
Authors: Rodríguez M. Mar , Pastor F. Javier , Sutton Deanna A. , Calvo Enrique , Fothergill Annette W. , Salas Valentina , Rinaldi Michael G. , Guarro Josep 
Published: February 2010

ABSTRACT

We have evaluated the
in vitro
activity of posaconazole (PSC) against 50 clinical strains of
Rhizopus oryzae
using a broth microdilution method, the Neo-Sensitabs tablet diffusion method, and minimal fungicidal concentration (MFC) determination. In general, PSC showed low MICs against this fungus, and the MICs correlated with the inhibition zone diameters. Most of the MFCs, however, were from 1 to 4 dilutions higher than their corresponding MICs. We then investigated the efficacies of several different doses of PSC in a murine model. All treatments began 24 h after challenge and lasted for 7 days. The drug was administered twice a day to mice infected with three strains that showed intermediate PSC susceptibility (MIC = 2 μg/ml) and three PSC-susceptible strains (MIC = 0.25 μg/ml). A dose of 10 mg/kg of body weight was ineffective, while doses of 20 and 30 mg/kg prolonged the survival of the mice. The 50 strains tested were segregated into two groups on the basis of the
in vitro
data. For the group with the most strains (85%), the strains had low PSC MICs, mice infected with the strains showed higher rates of survival (30 to 40%), and PSC was able to reduce the fungal load in the kidney and less regularly in the brain. For the second group (15% of the strains), the strains had intermediate PSC MICs, mice infected with the strains had lower survival rates (10 to 20%), and PSC treatment resulted in variable and no reductions in the fungal loads in the kidneys and brains, respectively.
Crystal Structure of the Narrow-Spectrum OXA-46 Class D β-Lactamase: Relationship between Active-Site Lysine Carbamylation and Inhibition by Polycarboxylates
Authors: Docquier Jean-Denis , Benvenuti Manuela , Calderone Vito , Giuliani Francesco , Kapetis Dimos , De Luca Filomena , Rossolini Gian Maria , Mangani Stefano 
Published: February 2010

ABSTRACTClass D β-lactamases represent a heterogeneous group of active-site serine β-lactamases that show an extraordinary panel of functional features and substrate profiles, thus representing relevant models for biochemical and structural studies. OXA-46 is a narrow-spectrum enzyme belonging to the OXA-2 subgroup which was found in aPseudomonas aeruginosaclinical isolate from northern Italy. In this work, we obtained the three-dimensional structure of OXA-46, which shows the overall fold of active serine β-lactamases and a dimeric quaternary structure. Significant differences with currently available structures of class D β-lactamases were found in the loops located close to the active site, which differ in length and conformation. Interestingly, the three subunits present in the asymmetric unit showed some structural heterogeneity, only one of which presented a carbamylated lysine recognized as an important functional feature of class D enzymes. The carbamylation state of residue Lys75 appeared to be associated with different shapes and dimensions of the active site. Moreover, a tartrate molecule from the crystallization buffer was found in the active site of the noncarbamylated subunits, which interacts with catalytically relevant residues. The OXA-46 crystal asymmetric units thus interestingly present the structures of the free carbamylated active site and of the ligand-bound uncarbamylated active site, offering the structural basis for investigating the potential of new scaffolds of β-lactamase inhibitors.
Occurrence of ST23 Complex Phylogroup A
Escherichia coli
Isolates Producing Extended-Spectrum AmpC β-Lactamase in a French Hospital
Authors: Crémet Lise , Caroff Nathalie , Giraudeau Cécile , Dauvergne Sandie , Lepelletier Didier , Reynaud Alain , Corvec Stéphane 
Published: February 2010

ABSTRACT

Extended-spectrum AmpC β-lactamase (ESAC)
Escherichia coli
producers were investigated over a 5-year period. Eleven isolates presenting a strong
ampC
promoter and different strategic AmpC mutations, including two newly described modifications (A292V and an L-A-A insertion at 295), were characterized. All the isolates belonged to phylogenetic group A and to the ST23 complex.
Stressor Exposure Disrupts Commensal Microbial Populations in the Intestines and Leads to Increased Colonization by
Citrobacter rodentium
Authors: Bailey Michael T. , Dowd Scot E. , Parry Nicola M. A. , Galley Jeffrey D. , Schauer David B. , Lyte Mark 
Published: February 2010

ABSTRACT

The gastrointestinal tract is colonized by an enormous array of microbes that are known to have many beneficial effects on the host. Previous studies have indicated that stressor exposure can disrupt the stability of the intestinal microbiota, but the extent of these changes, as well as the effects on enteric infection, has not been well characterized. In order to examine the ability of stressors to induce changes in the gut microbiota, we exposed mice to a prolonged restraint stressor and then characterized microbial populations in the intestines using both traditional culture techniques and bacterial tag-encoded FLX amplicon pyrosequencing (bTEFAP). Exposure to the stressor led to an overgrowth of facultatively anaerobic microbiota while at the same time significantly reducing microbial richness and diversity in the ceca of stressed mice. Some of these effects could be explained by a stressor-induced reduction in the relative abundance of bacteria in the family
Porphyromonadaceae
. To determine whether these alterations would lead to increased pathogen colonization, stressed mice, as well as nonstressed controls, were challenged orally with the enteric murine pathogen
Citrobacter rodentium
. Exposure to the restraint stressor led to a significant increase in
C. rodentium
colonization over that in nonstressed control mice. The increased colonization was associated with increased tumor necrosis factor alpha (TNF-α) gene expression in colonic tissue. Together, these data demonstrate that a prolonged stressor can significantly change the composition of the intestinal microbiota and suggest that this disruption of the microbiota increases susceptibility to an enteric pathogen.
Examination of Type IV Pilus Expression and Pilus-Associated Phenotypes in
Kingella kingae
Clinical Isolates
Authors: Kehl-Fie Thomas E. , Porsch Eric A. , Yagupsky Pablo , Grass Elizabeth A. , Obert Caroline , Benjamin Daniel K. , St. Geme Joseph W. 
Published: February 2010

ABSTRACT

Kingella kingae
is a gram-negative bacterium that is being recognized increasingly as a cause of septic arthritis and osteomyelitis in young children. Previous work established that
K. kingae
expresses type IV pili that mediate adherence to respiratory epithelial and synovial cells. PilA1 is the major pilus subunit in
K. kingae
type IV pili and is essential for pilus assembly. To develop a better understanding of the role of
K. kingae
type IV pili during colonization and invasive disease, we examined a collection of clinical isolates for pilus expression and
in vitro
adherence. In addition, in a subset of isolates we performed nucleotide sequencing to assess the level of conservation of PilA1. The majority of respiratory and nonendocarditis blood isolates were piliated, while the majority of joint fluid, bone, and endocarditis blood isolates were nonpiliated. The piliated isolates formed either spreading/corroding or nonspreading/noncorroding colonies and were uniformly adherent, while the nonpiliated isolates formed domed colonies and were nonadherent. PilA1 sequence varied significantly from strain to strain, resulting in substantial variability in antibody reactivity. These results suggest that type IV pili may confer a selective advantage on
K. kingae
early in infection and a selective disadvantage on
K. kingae
at later stages in the pathogenic process. We speculate that PilA1 is immunogenic during natural infection and undergoes antigenic variation to escape the immune response.
UpaH Is a Newly Identified Autotransporter Protein That Contributes to Biofilm Formation and Bladder Colonization by Uropathogenic
Escherichia coli
CFT073
Authors: Allsopp Luke P. , Totsika Makrina , Tree Jai J. , Ulett Glen C. , Mabbett Amanda N. , Wells Timothy J. , Kobe Bostjan , Beatson Scott A. , Schembri Mark A. 
Published: February 2010

ABSTRACT

Escherichia coli
is the primary cause of urinary tract infection (UTI) in the developed world. The major factors associated with virulence of uropathogenic
E. coli
(UPEC) are fimbrial adhesins, which mediate specific attachment to host receptors and trigger innate host responses. Another group of adhesins is represented by the autotransporter (AT) subgroup of proteins. In this study, we identified a new AT-encoding gene, termed
upaH
, present in a 6.5-kb unannotated intergenic region in the genome of the prototypic UPEC strain CFT073. Cloning and sequencing of the
upaH
gene from CFT073 revealed an intact 8.535-kb coding region, contrary to the published genome sequence. The
upaH
gene was widely distributed among a large collection of UPEC isolates as well as the
E. coli
Reference (ECOR) strain collection. Bioinformatic analyses suggest β-helix as the predominant structure in the large N-terminal passenger (α) domain and a 12-strand β-barrel for the C-terminal β-domain of UpaH. We demonstrated that UpaH is expressed at the cell surface of CFT073 and promotes biofilm formation. In the mouse UTI model, deletion of the
upaH
gene in CFT073 and in two other UPEC strains did not significantly affect colonization of the bladder in single-challenge experiments. However, in competitive colonization experiments, CFT073 significantly outcompeted its
upaH
isogenic mutant strain in urine and the bladder.
Concomitant Infection Decreases the Malaria Burden but Escalates Relapsing Fever Borreliosis
Authors: Lundqvist Jenny , Larsson Christer , Nelson Maria , Andersson Marie , Bergström Sven , Persson Cathrine 
Published: February 2010

ABSTRACT

About 500 million cases of malaria occur annually. However, a substantial number of patients who actually have relapsing fever (RF)
Borrelia
infection can be misdiagnosed with malaria due to similar manifestations and geographic distributions of the two diseases. More alarmingly, a high prevalence of concomitant infections with malaria and RF
Borrelia
has been reported. Therefore, we used a mouse model to study the effects of such mixed infection. We observed a 21-fold increase in spirochete titers, whereas the numbers of parasitized erythrocytes were reduced 15-fold. This may be explained by polarization of the host immune response toward the intracellular malaria parasite, resulting in unaffected extracellular spirochetes and hosts that succumb to sepsis. Mixed infection also resulted in severe malaria anemia with low hemoglobin levels, even though the parasite counts were low. Overall, coinfected animals had a higher fatality rate and shorter time to death than those with either malaria or RF single infection. Furthermore, secondary malaria infection reactivated a quiescent RF brain infection, which is the first evidence of a clinically and biologically relevant cue for reactivation of RF
Borrelia
infection. Our study highlights the importance of investigating concomitant infections
in vivo
to elucidate the immune responses that are involved in the clinical outcome.
Extracellular Vesicles from
Cryptococcus neoformans
Modulate Macrophage Functions
Authors: Oliveira Débora L. , Freire-de-Lima Célio G. , Nosanchuk Joshua D. , Casadevall Arturo , Rodrigues Marcio L. , Nimrichter Leonardo 
Published: February 2010

ABSTRACT

Cryptococcus neoformans
and distantly related fungal species release extracellular vesicles that traverse the cell wall and contain a varied assortment of components, some of which have been associated with virulence. Previous studies have suggested that these extracellular vesicles are produced
in vitro
and during animal infection, but the role of vesicular secretion during the interaction of fungi with host cells remains unknown. In this report, we demonstrate by fluorescence microscopy that mammalian macrophages can incorporate extracellular vesicles produced by
C. neoformans
. Incubation of cryptococcal vesicles with murine macrophages resulted in increased levels of extracellular tumor necrosis factor alpha (TNF-α), interleukin-10 (IL-10), and transforming growth factor β (TGF-β). Vesicle preparations also resulted in a dose-dependent stimulation of nitric oxide production by phagocytes, suggesting that vesicle components stimulate macrophages to produce antimicrobial compounds. Treated macrophages were more effective at killing
C. neoformans
yeast. Our results indicate that the extracellular vesicles of
C. neoformans
can stimulate macrophage function, apparently activating these phagocytic cells to enhance their antimicrobial activity. These results establish that cryptococcal vesicles are biologically active.
NONSTABILITY OF THE IDEALS OF THE CORONA ALGEBRA OF A SEPARABLE STABLE PRIME C*-ALGEBRA
Authors: NG PING WONG 
Published: February 2010

Let [Formula: see text] be a separable stable and prime C*-algebra. We show that every proper nontrivial ideal in [Formula: see text] (and hence every proper ideal in [Formula: see text] which properly contains [Formula: see text]) is not stable.Some consequences are counterexamples naturally occuring, in the non-σ-unital case, to Zhang's Dichotomy as well as the Hjelmborg–Rørdam theory of stability.