bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synergy between Efflux Pump CmeABC and Modifications in Ribosomal Proteins L4 and L22 in Conferring Macrolide Resistance in
Campylobacter jejuni
and
Campylobacter coli
Authors: Cagliero Cédric , Mouline Christian , Cloeckaert Axel , Payot Sophie 
Published: October 2006

ABSTRACT

Macrolide-resistant mutants of
Campylobacter jejuni
and
Campylobacter coli
were selected in vitro using erythromycin and tylosin. These mutants exhibited modifications in the ribosomal proteins L4 (G74D) and L22 (insertions at position 86 or 98). A synergy between the CmeABC efflux pump and these modifications in conferring macrolide resistance was observed.
Amino Acid Substitutions in Mosaic Penicillin-Binding Protein 2 Associated with Reduced Susceptibility to Cefixime in Clinical Isolates of
Neisseria gonorrhoeae
Authors: Takahata Sho , Senju Nami , Osaki Yumi , Yoshida Takuji , Ida Takashi 
Published: October 2006

ABSTRACT

The molecular mechanisms of reduced susceptibility to cefixime in clinical isolates of
Neisseria gonorrhoeae
, particularly amino acid substitutions in mosaic penicillin-binding protein 2 (PBP2), were examined. The complete sequence of
ponA
,
penA
, and
por
genes, encoding, respectively, PBP1, PBP2, and porin, were determined for 58 strains isolated in 2002 from Japan. Replacement of leucine 421 by proline in PBP1 and the mosaic-like structure of PBP2 were detected in 48 strains (82.8%) and 28 strains (48.3%), respectively. The presence of mosaic PBP2 was the main cause of the elevated cefixime MIC (4- to 64-fold). In order to identify the mutations responsible for the reduced susceptibility to cefixime in isolates with mosaic PBP2,
penA
genes with various mutations were transferred to a susceptible strain by genetic transformation. The susceptibility of partial recombinants and site-directed mutants revealed that the replacement of glycine 545 by serine (G545S) was the primary mutation, which led to a two- to fourfold increase in resistance to cephems. Replacement of isoleucine 312 by methionine (I312M) and valine 316 by threonine (V316T), in the presence of the G545S mutation, reduced susceptibility to cefixime, ceftibuten, and cefpodoxime by an additional fourfold. Therefore, three mutations (G545S, I312M, and V316T) in mosaic PBP2 were identified as the amino acid substitutions responsible for reduced susceptibility to cefixime in
N. gonorrhoeae
.
In Vitro Antianaerobic Activity of DX-619, a New Des-Fluoro(6)Quinolone
Authors: Tanaka Kaori , Mikamo Hiroshige , Nakao Ken'ichi , Watanabe Kunitomo 
Published: October 2006

ABSTRACT

The
in vitro activity of DX-619, a new des-F(6) quinolone, against
anaerobic bacteria was evaluated. DX-619 showed potent activity against
Bacteroides
,
Prevotella
,
Fusobacterium
,
Micromonas
,
Actinomyces
, and
Clostridium
spp., with MIC
50
s/MIC
90
s of ≤0.03 to
0.25/≤0.03 to 1 μg/ml, respectively. DX-619 was also
active against imipenem-resistant
Bacteroides
spp., with
MIC
50
s/MIC
90
s of 0.25/1 μg/ml,
respectively.
Studies on the Mode of Action of the Antifungal Hexapeptide PAF26
Authors: Muñoz Alberto , López-García Belén , Marcos Jose F. 
Published: October 2006

ABSTRACT

The small antimicrobial peptide PAF26 (Ac-RKKWFW-NH
2
) has been identified by a combinatorial approach and shows preferential activity toward filamentous fungi. In this work, we investigated the mode of action and inhibitory effects of PAF26 on the fungus
Penicillium digitatum
. The dye Sytox Green was used to demonstrate that PAF26 induced cell permeation. However, microscopic observations showed that sub-MIC concentrations of PAF26 produced both alterations of hyphal morphology (such as altered polar growth and branching) and chitin deposition in areas of no detectable permeation. Analysis of dose-response curves of inhibition and permeation suggested that growth inhibition is not solely a consequence of permeation. In order to shed light on the mode of PAF26 action, its antifungal properties were compared with those of melittin, a well-known pore-forming peptide that kills through cytolysis. While the 50% inhibitory concentrations and MICs of the two peptides against
P. digitatum
mycelium were comparable, they differed markedly in their fungicidal activities toward conidia and their hemolytic activities toward human red blood cells. Kinetic studies showed that melittin quickly induced
Penicillium
cell permeation, while PAF26-induced Sytox Green uptake was significantly slower and less efficient. Therefore, the ultimate growth inhibition and morphological alterations induced by PAF26 for
P. digitatum
are not likely a result of conventional pore formation. Fluorescently labeled PAF26 was used to demonstrate its specific in vivo interaction and translocation inside germ tubes and hyphal cells, at concentrations as low as 0.3 μM (20 times below the MIC), at which no inhibitory, morphological, or permeation effects were observed. Interestingly, internalized PAF26 could bind to cellular RNAs, since in vitro nonspecific RNA binding activity of PAF26 was demonstrated by electrophoretic mobility shift assays. We propose that PAF26 is a short, de novo-designed penetratin-type peptide that has multiple detrimental effects on target fungi, which ultimately result in permeation and killing.
In Vitro Activities of Tritrpticin Alone and in Combination with Other Antimicrobial Agents against
Pseudomonas aeruginosa
Authors: Cirioni Oscar , Giacometti Andrea , Silvestri Carmela , Della Vittoria Agnese , Licci Alberto , Riva Alessandra , Scalise Giorgio 
Published: October 2006

ABSTRACT

The in vitro activity of the cathelicidin tritrpticin was investigated against multidrug-resistant
Pseudomonas aeruginosa
. The isolates were susceptible to the peptide at concentrations of 0.50 to 8 mg/liter. Tritrpticin completely inhibits lipopolysaccharide procoagulant activity at a 10 μM concentration. Fractionary inhibitory concentration indexes (0.385, 0.312, and 0.458) demonstrated synergy between the peptide and β-lactams.
Unexpected Link between Iron and Drug Resistance of
Candida
spp.: Iron Depletion Enhances Membrane Fluidity and Drug Diffusion, Leading to Drug-SusceptibleCells
Authors: Prasad Tulika , Chandra Aparna , Mukhopadhyay Chinmay K. , Prasad Rajendra 
Published: October 2006

ABSTRACT

Inthis study, we show that iron depletion in
Candida
albicans
with bathophenanthrolene disulfonic acid and
ferrozine as chelators enhanced its sensitivity to several drugs,
including the most common antifungal, fluconazole (FLC). Several other
species of
Candida
also displayed increased sensitivity to FLC
because of iron restriction. Iron uptake mutations, namely,Δ
ftr1
and Δ
ftr2
, as well as the
copper transporter mutation Δ
ccc2
, which affects
high-affinity iron uptake in
Candida
, produced increased
sensitivity to FLC compared to that of the wild type. The effect of
iron depletion on drug sensitivity appeared to be independent of the
efflux pump proteins Cdr1p and Cdr2p. We found that iron deprivation
led to lowering of membrane ergosterol by 15 to 30%. Subsequently,
fluorescence polarization measurements also revealed that
iron-restricted
Candida
cells displayed a 29 to 40% increase
in membrane fluidity, resulting in enhanced passive diffusion of the
drugs. Northern blot assays revealed that the
ERG11
gene was
considerably down regulated in iron-deprived cells, which might account
for the lowered ergosterol content. Our results show a close
relationship between cellular iron and drug susceptibilities of
C. albicans
. Considering that multidrug resistance is
a manifestation of multifactorial phenomena, the influence of cellular
iron on the drug susceptibilities of
Candida
suggests iron as
yet another novel determinant of multidrug
resistance.
Novel
Pseudomonas aeruginosa
Quorum-Sensing Inhibitors Identified in an Ultra-High-Throughput Screen
Authors: Müh Ute , Schuster Martin , Heim Roger , Singh Ashvani , Olson Eric R. , Greenberg E. Peter 
Published: October 2006

ABSTRACT

The opportunistic pathogen
Pseudomonas aeruginosa
has two complete acyl-homoserine lactone (acyl-HSL) signaling systems, LasR-LasI and RhlR-RhlI. LasI catalyzes the synthesis of
N
-3-oxododecanoyl homoserine lactone (3OC12-HSL), and LasR is a transcription factor that requires 3OC12-HSL as a ligand. RhlI catalyzes the synthesis of
N
-butanoyl homoserine lactone (C
4
), and RhlR is a transcription factor that responds to C
4
. LasR and RhlR control the transcription of hundreds of
P. aeruginosa
genes, many of which are critical virulence determinants, and LasR is required for RhlR function. We developed an ultra-high-throughput cell-based assay to screen a library of approximately 200,000 compounds for inhibitors of LasR-dependent gene expression. Although the library contained a large variety of chemical structures, the two best inhibitors resembled the acyl-homoserine lactone molecule that normally binds to LasR. One compound, a tetrazole with a 12-carbon alkyl tail designated PD12, had a 50% inhibitory concentration (IC
50
) of 30 nM. The second compound, V-06-018, had an IC
50
of 10 μM and is a phenyl ring with a 12-carbon alkyl tail. A microarray analysis showed that both compounds were general inhibitors of quorum sensing, i.e., the expression levels of most LasR-dependent genes were affected. Both compounds also inhibited the production of two quorum-sensing-dependent virulence factors, elastase and pyocyanin. These compounds should be useful for studies of LasR-dependent gene regulation and might serve as scaffolds for the identification of new quorum-sensing modulators.
Search for Cyclodextrin-Based Inhibitors of Anthrax Toxins: Synthesis, Structural Features, and Relative Activities
Authors: Karginov Vladimir A. , Nestorovich Ekaterina M. , Yohannes Adiamseged , Robinson Tanisha M. , Fahmi Nour Eddine , Schmidtmann Frank , Hecht Sidney M. , Bezrukov Sergey M. 
Published: October 2006

ABSTRACT
Recently, using structure-inspired drug design, we demonstrated that aminoalkyl derivatives of β-cyclodextrin inhibited anthrax lethal toxin action by blocking the transmembrane pore formed by the protective antigen (PA) subunit of the toxin. In the present study, we evaluate a series of new β-cyclodextrin derivatives with the goal of identifying potent inhibitors of anthrax toxins. Newly synthesized hepta-6-thioaminoalkyl and hepta-6-thioguanidinoalkyl derivatives of β-cyclodextrin with alkyl spacers of various lengths were tested for the ability to inhibit cytotoxicity of lethal toxin in cells as well as to block ion conductance through PA channels reconstituted in planar bilayer lipid membranes. Most of the tested derivatives were protective against anthrax lethal toxin action at low or submicromolar concentrations. They also blocked ion conductance through PA channels at concentrations as low as 0.1 nM. The activities of the derivatives in both cell protection and channel blocking were found to depend on the length and chemical nature of the substituent groups. One of the compounds was also shown to block the edema toxin activity. It is hoped that these results will help to identify a new class of drugs for anthrax treatment, i.e., drugs that block the pathway for toxin translocation into the cytosol, the PA channel.
Variant
Salmonella
Genomic Island 1-L Antibiotic Resistance Gene Cluster in
Salmonella enterica
Serovar Newport
Authors: Cloeckaert Axel , Praud Karine , Doublet Benoît , Demartin Marie , Weill François-Xavier 
Published: October 2006

ABSTRACT

We report a new
Salmonella
genomic island 1 variant antibiotic resistance gene cluster called SGI1-L in a
Salmonella enterica
serovar Newport isolate containing a
dfrA15
gene cassette conferring resistance to trimethoprim. The isolate carried another class 1 integron containing the
aacC5
and
aadA7
gene cassettes conferring resistance to gentamicin and streptomycin/spectinomycin, respectively.
Integration of Pharmacokinetic and Pharmacodynamic Indices of Marbofloxacin in Turkeys
Authors: Haritova Aneliya Milanova , Rusenova Nikolina Velizarova , Parvanov Parvan Rusenov , Lashev Lubomir Dimitrov , Fink-Gremmels Johanna 
Published: October 2006

ABSTRACT

Fluoroquinolones are extensively used in the treatment of systemic bacterial infections in poultry, including systemic
Escherichia coli
bacillosis, which is a common disease in turkey flocks. Marbofloxacin has been licensed for use in various mammalian species, but not as yet for turkeys, although its kinetic properties distinguish it from other fluoroquinolones. For example, the longer half-life of marbofloxacin in many animal species has been appreciated in veterinary practice. It is generally accepted that, for fluoroquinolones, the optimal dose should be estimated on the basis of the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the drug under consideration. Knowledge of these specific data for the target animal species allows the establishment of an integrated PK-PD model that is of high predictive value. In the present study, the antibacterial efficacy (PD indices) against a field isolate of
Escherichia coli
O78/K80 was investigated ex vivo following oral and intravenous administration of marbofloxacin to turkeys (breed BUT 9; six animals per group) at a dose of 2 mg/kg of body weight (BW). At the same time, the serum concentrations of marbofloxacin were measured at different time intervals by a standardized high-performance liquid chromatography method, allowing the calculation of the most relevant kinetic parameters (PK parameters). The in vitro serum inhibitory activity of marbofloxacin against the selected
E. coli
strain, O78/K80, was 0.5 μg/ml in the blood serum of turkeys, and the ratio of the maximum concentration of the drug in serum to the serum inhibitory activity was 1.34. The lowest ratio of the measured serum concentration multiplied by the incubation period of 24 h to the serum inhibitory activity required for bacterial elimination was lower than the ratio of the area under the serum concentration-time curve (AUC) to the serum inhibitory activity. These first results suggested that the recommended dose of 2 mg/kg BW of marbofloxacin is sufficient to achieve a therapeutic effect in diseased animals. However, considering the risk of resistance induction, the applied dose should be equal to an AUC/MIC of >125, the generally recommended dose for all fluoroquinolones. According to the PK-PD results presented here, a dose of 3.0 to 12.0 mg/kg BW per day would be needed to meet this criterion. In conclusion, the results of the present study provide the rationale for an optimal dose regimen for marbofloxacin in turkeys and hence should form the basis for dose selection in forthcoming clinical trials.
Postantibiotic Effect of Ceftobiprole against 12 Gram-Positive Organisms
Authors: Pankuch G. A. , Appelbaum P. C. 
Published: October 2006

ABSTRACT
The in vitro postantibiotic effects (PAEs), postantibiotic sub-MIC effects (PA-SMEs), and sub-MIC effects of ceftobiprole were determined for 12 gram-positive organisms. Pneumococcal, staphylococcal, and enterococcal PAEs were 1.4 to 3.1 h, 0 to 1.8 h, and 0 to 0.9 h, respectively. The PA-SMEs (0.4 times the MIC) for pneumococci, staphylococci, and enterococci were 4.8 to >10.3 h, 1.5 to 9.6 h, and 3.8 to >10.7 h, respectively.
Prevalence of Mutations Associated with Higher Levels of Sulfadoxine-Pyrimethamine Resistance in
Plasmodium falciparum
Isolates from Car Nicobar Island and Assam, India
Authors: Ahmed Anwar , Lumb Vanshika , Das Manoj K. , Dev Vas , Wajihullah  , Sharma Yagya D. 
Published: October 2006

ABSTRACT

To assess sulfadoxine and pyrimethamine resistance (SPR), we describe here the dihydropteroate synthetase (DHPS) mutations among the
Plasmodium falciparum
isolates in which dihydrofolate reductase (DHFR) mutations had recently been described by us (A. Ahmed, M. K. Das, V. Dev, M. A. Saifi, Wajihullah, and Y. D. Sharma, Antimicrob. Agents Chemother. 50:1546-1549, 2006). A majority of isolates from Car Nicobar island showed double DHPS mutations, whereas a majority of isolates from Uttar Pradesh (U.P.) and Assam contained the wild-type DHPS. Based on DHFR-DHPS mutations, the expected level of SPR was lowest in U.P., higher in Assam, and highest in Car Nicobar, suggesting that a region-wise drug policy is needed in India.
Population Analysis of Weight-, Age-, and Sex-Related Differences in the Pharmacokinetics of Lopinavir in Children from Birth to 18 Years
Authors: Jullien Vincent , Urien Saïk , Hirt Déborah , Delaugerre Constance , Rey Elisabeth , Teglas Jean-Paul , Vaz Paula , Rouzioux Christine , Chaix Marie-Laure , Macassa Eugenia , Firtion Ghislaine , Pons Gérard , Blanche Stéphane , Tréluyer Jean-Marc 
Published: October 2006

ABSTRACT

The pharmacokinetics of lopinavir were investigated by the use of a population approach performed with the nonlinear mixed effect modeling program NONMEM and 157 children ranging in age from 3 days to 18 years. The pharmacokinetics of lopinavir were well described by a one-compartment model in which the absorption and the elimination rate constants were equal. Typical population estimates of the apparent volume of distribution (
V
/
F
) and plasma clearance (CL/
F
) were 24.6 liters and 2.58 liters/h, respectively. The lopinavir
V
/
F
and CL/
F
were both related to body weight (BW), with an important increase in weight-normalized CL/
F
for the lowest BW. Combined treatment with lopinavir and nevirapine was found to increase the CL/
F
. The lopinavir CL/
F
was also age and sex related, as a 39% increase was observed after the age of 12 years for boys compared to the CL/
F
for girls. The consequences of these pharmacokinetic discrepancies and the necessity to modify the currently recommended dosage regimen should be further investigated.
A Small Subpopulation of Blastospores in
Candida albicans
Biofilms Exhibit Resistance to Amphotericin B Associated with Differential Regulation of Ergosterol and
β
-1,6-Glucan Pathway Genes
Authors: Khot Prasanna D. , Suci Peter A. , Miller R. Lance , Nelson Raoul D. , Tyler Bonnie J. 
Published: October 2006

ABSTRACT

The resistance of
Candida albicans
biofilms to a broad spectrum of antimicrobial agents has been well documented. Biofilms are known to be heterogeneous, consisting of microenvironments that may induce formation of resistant subpopulations. In this study we characterized one such subpopulation.
C. albicans
biofilms were cultured in a tubular flow cell (TF) for 36 h. The relatively large shear forces imposed by draining the TF removed most of the biofilm, which consisted of a tangled mass of filamentous forms with associated clusters of yeast forms. This portion of the biofilm exhibited the classic architecture and morphological heterogeneity of a
C. albicans
biofilm and was only slightly more resistant than either exponential- or stationary-phase planktonic cells. A submonolayer fraction of blastospores that remained on the substratum was resistant to 10 times the amphotericin B dose that eliminated the activity of the planktonic populations. A comparison between planktonic and biofilm populations of transcript abundance for genes coding for enzymes in the ergosterol (
ERG1
, -
3
, -
5
, -
6
, -
9
, -
11
, and -
25
) and β-1,6-glucan (
SKN
and
KRE1
, -
5
, -
6
, and -
9
) pathways was performed by quantitative RT-PCR. The results indicate a possible association between the high level of resistance exhibited by the blastospore subpopulation and differential regulation of
ERG1
,
ERG25
,
SKN1
, and
KRE1
. We hypothesize that the resistance originates from a synergistic effect involving changes in both the cell membrane and the cell wall.
Methodological Issues in the Assessment of Antimalarial Drug Treatment: Analysis of 13 Studies in Eight African Countries from 2001 to 2004
Authors: Guthmann Jean-Paul , Pinoges Loretxu , Checchi Francesco , Cousens Simon , Balkan Suna , van Herp Michel , Legros Dominique , Olliaro Piero 
Published: October 2006

ABSTRACT
The objectives of these analyses were to assess the feasibility of the latest WHO recommendations (28-day follow-up with PCR genotyping) for the assessment of antimalarial drug efficacy in vivo and to examine how different statistical approaches affect results. We used individual-patient data from 13 studies of uncomplicated pediatric falciparum malaria conducted in sub-Saharan Africa, using chloroquine (CQ), sulfadoxine/pyrimethamine (SP), or amodiaquine (AQ). We assessed the use effectiveness and test performance of PCR genotyping in distinguishing recurrent infections. In analyzing data, we compared (i) the risk of failure on target days (days 14 and 28) by using Kaplan-Meier and per-protocol evaluable patient analyses, (ii) PCR-corrected results allowing (method 1) or excluding (method 2) new infections, (iii) and day 14 versus day 28 results. Of the 2,576 patients treated, 2,287 (89%) were evaluable on day 28. Of the 695 recurrences occurring post-day 14, 650 could be processed and 584 were resolved (PCR use effectiveness, 84%; test performance, 90%). The risks of failure on day 28 with Kaplan-Meier and evaluable-patient analyses tended to be generally close (except in smaller studies) because the numbers of dropouts were minimal, but attrition rates on day 28 were higher with the latter method. Method 2 yielded higher risks of failure than method 1. Extending observation to 28 days produced higher estimated risks of failure for SP and AQ but not for CQ (high failure rates by day 14). Results support the implementation of the current WHO protocol and favor analyzing PCR-corrected outcomes by Kaplan-Meier analysis (which allows for dropouts) and retaining new infections (which minimizes losses).
Maximal lipidic power in high competitive level triathletes and cyclists
Authors: González-Haro C , Galilea P A , González-de-Suso J M , Drobnic F , Escanero J F 
Published: October 2006

Objective:To describe the fat-oxidation rate in triathlon and different modalities of endurance cycling.Methods:34 endurance athletes (15 male triathletes, 4 female triathletes, 11 road cyclists and 4 male mountain bikers) underwent a progressive cycloergometer test until exhaustion. Relative work intensity (VO2max), minimal lactate concentration (La−min), lactic threshold, individual lactic threshold (ILT), maximal fat-oxidation rate (Fatmax, Fatmaxzone) and minimal fat-oxidation rate (Fatmin) were determined in each of the groups and were compared by means of one-way analysis of variance.Results:No significant differences were found for Fatmax, Fatminor for the Fatmaxzone expressed as fat oxidation rate (g/min). Intensities −20%, −10% and −5% Fatmaxwere significantly lower for mountain bikers with respect to road cyclists and female triathletes, expressed as % VO2max. Intensities 20%, 10% and 5% Fatmaxwere significantly lower for mountain bikers with respect to male triathletes and female triathletes, and for male triathletes in comparison with female triathletes, expressed as % VO2max. Lactic threshold and La−mindid not show significant differences with respect to Fatmax. Lactic threshold was found at the same VO2maxwith respect to the higher part of the Fatmaxzone, and La−minat the same VO2maxwith respect to the lower part of the Fatmaxzone.Conclusions:The VO2maxof Fatmaxand the Fatmaxzone may explain the different endurance adaptations of the athletes according to their sporting discipline. Lactic threshold and La−minwere found at different relative work intensities with respect to those of Fatmaxeven though they belonged to the Fatmaxzone.