bluuebunny/crossref_metadata_2025_split huggingface dataset:
Physicochemical Properties That Enhance Discriminative Antibacterial Activity of Short Dermaseptin Derivatives
Authors: Rotem Shahar , Radzishevsky Inna , Mor Amram 
Published: July 2006

ABSTRACTAntimicrobial peptides are widely believed to exert their effects by nonspecific mechanisms. We assessed the extent to which physicochemical properties can be exploited to promote discriminative activity by manipulating the N-terminal sequence of the 13-mer dermaseptin derivative K4-S4(1-13) (P). Inhibitory activity determined in culture media against 16 strains of bacteria showed that when its hydrophobicity and charge were changed, P became predominantly active against either gram-positive or gram-negative bacteria. Thus, conjugation of various aminoacyl-lysin moieties (e.g., aminohexyl-K-P) led to inactivity against gram-positive bacteria (MIC50> 50 μM) but potent activity against gram-negative bacteria (MIC50, 6.2 μM). Conversely, conjugation of equivalent acyls to the substituted analog M4-S4(1-13) (e.g., hexyl-M4-P) led to inactivity against gram-negative bacteria (MIC50> 50 μM) but potent activity against gram-positive bacteria (MIC50, 3.1 μM). Surface plasmon resonance experiments, used to investigate peptides' binding properties to lipopolysaccharide-containing idealized phospholipid membranes, suggest that although the acylated derivatives have increased lipophilic properties with parallel antibacterial behavior, hydrophobic derivatives are prevented from reaching the cytoplasmic membranes of gram-negative bacteria. Moreover, unlike modifications that enhanced the activity against gram-positive bacteria, which also enhanced hemolysis, we found that modifications that enhanced activity against gram-negative bacteria generally reduced hemolysis. Thus, compared with the clinically tested peptides MSI-78 and IB-367, the dermaseptin derivative aminohexyl-K-P performed similarly in terms of potency and bactericidal kinetics but was significantly more selective in terms of discrimination between bacteria and human erythrocytes. Overall, the data suggest that similar strategies maybe useful to derive potent and safe compounds from known antimicrobial peptides.
Contribution of Penicillin-Binding Protein Homologs to Antibiotic Resistance, Cell Morphology, and Virulence of
Listeria monocytogenes
EGDe
Authors: Guinane Caitriona M. , Cotter Paul D. , Ross R. Paul , Hill Colin 
Published: July 2006

ABSTRACT

Seven open reading frames, annotated as potential penicillin-binding-protein-encoding genes (lmo0441, lmo0540, lmo1438, lmo1892, lmo2039, lmo2229, and lmo2754), were targeted for insertional mutagenesis in
Listeria monocytogenes
EGDe. These genes were found to contribute in various degrees to β-lactam resistance, cell morphology, or the virulence potential of this organism.
Potential Role of
Veillonella
spp. as a Reservoir of Transferable Tetracycline Resistance in the Oral Cavity
Authors: Ready D. , Pratten J. , Roberts A. P. , Bedi R. , Mullany P. , Wilson M. 
Published: July 2006

ABSTRACT

Twelve out of 96
Veillonella
spp. isolated from oral samples harbored tetracycline resistance genes. The most common resistance gene was
tet
(M). A
tet
(M)-positive
Veillonella dispar
strain was shown to transfer a Tn
916
-like element to four
Streptococcus
spp. by conjugation at a frequency of 5.2 × 10
−6
to 4.5 × 10
−5
per recipient.
In Vitro Activities of Ceftobiprole, Tigecycline, Daptomycin, and 19 Other Antimicrobials against Methicillin-Resistant
Staphylococcus aureus
Strains from a National Survey of Belgian Hospitals
Authors: Denis Olivier , Deplano Ariane , Nonhoff Claire , Hallin Marie , De Ryck Raf , Vanhoof Raymond , De Mendonça Ricardo , Struelens Marc J. 
Published: July 2006

ABSTRACT

The in vitro activities of 22 antimicrobial agents, including ceftobiprole, daptomycin, and tigecycline, against 511 methicillin-resistant
Staphylococcus aureus
(MRSA) isolates from 112 Belgian hospitals were studied by using the CLSI agar dilution method. Isolates were characterized by pulsed-field gel electrophoresis (PFGE) analysis and by PCR detection of determinants of resistance to aminoglycosides, macrolides-lincosamides-streptogramins, and tetracyclines. A representative set of isolates with different PFGE genotypes was further characterized by multilocus sequence typing, determination of staphylococcal cassette chromosome
mec
(SCC
mec
) type, and multiplex PCR for toxic shock syndrome type 1 (TSST-1) and Panton-Valentine leukocidin genes. MRSA isolates belonged to nine epidemic MRSA clones, of which sequence type 45 (ST45)-SCC
mec
IV and ST8-SCC
mec
IV were predominant, accounting for 49 and 20% of isolates, respectively. The distribution of antimicrobial resistance and TSST-1 genes was strongly linked to clonal types. Ceftobiprole, daptomycin, and tigecycline showed high activity against all isolates of these sporadic and epidemic MRSA clones, as indicated by MIC
90
s of 2 mg/liter, 0.5 mg/liter, and 0.25 mg/liter, respectively. The MIC distribution of daptomycin and tigecycline was not different in isolates with decreased susceptibility to glycopeptides or tetracyclines, respectively. Ceftobiprole MICs were not correlated with oxacillin and cefoxitin MICs. These data indicate excellent activity of the newly developed agents ceftobiprole, daptomycin, and tigecycline against MRSA isolates recently recovered from hospitalized patients in Belgium, supporting their therapeutic potential for nosocomial MRSA infections.
Dual Effects of Plant Steroidal Alkaloids on
Saccharomycescerevisiae
Authors: Simons Veronika , Morrissey John P. , Latijnhouwers Maita , Csukai Michael , Cleaver Adam , Yarrow Carol , Osbourn Anne 
Published: July 2006

ABSTRACT

Many
plant species accumulate sterols and triterpenes as antimicrobial
glycosides. These secondary metabolites (saponins) provide built-in
chemical protection against pest and pathogen attack and can also
influence induced defense responses. In addition, they have a variety
of important pharmacological properties, including anticancer activity.
The biological mechanisms underpinning the varied and diverse effects
of saponins on microbes, plants, and animals are only poorly understood
despite the ecological and pharmaceutical importance of this major
class of plant secondary metabolites. Here we have exploited budding
yeast (
Saccharomyces cerevisiae
) to investigate the effects of
saponins on eukaryotic cells. The tomato steroidal glycoalkaloidα
-tomatine has antifungal activity towards yeast, and this
activity is associated with membrane permeabilization. Removal of a
single sugar from the tetrasaccharide chain of α-tomatine
results in a substantial reduction in antimicrobial activity.
Surprisingly, the complete loss of sugars leads to enhanced antifungal
activity. Experiments with α-tomatine and its aglycone
tomatidine indicate that the mode of action of tomatidine towards yeast
is distinct from that of α-tomatine and does not involve
membrane permeabilization. Investigation of the effects of tomatidine
on yeast by gene expression and sterol analysis indicate that
tomatidine inhibits ergosterol biosynthesis. Tomatidine-treated cells
accumulate zymosterol rather than ergosterol, which is
consistent with inhibition of the sterol C
24
methyltransferase Erg6p. However,
erg6
and
erg3
mutants (but not
erg2
mutants) have enhanced resistance to
tomatidine, suggesting a complex interaction of
erg
mutations,
sterol content, and tomatidine
resistance.
Differential Gene Expression in Response to Exposure to Antimycobacterial Agents and Other Stress Conditions among SevenMycobacterium tuberculosis whiB-Like Genes
Authors: Geiman Deborah E. , Raghunand Tirumalai R. , Agarwal Nisheeth , Bishai William R. 
Published: July 2006

ABSTRACTThe sevenMycobacterium tuberculosis whiB-like genes encode small proteins postulated to be transcriptional regulators. A systematic real-time reverse transcription-PCR analysis following exposure to antibiotics and a variety of growth and in vitro stress conditions indicates differential, and in some cases dramatic, transcription modulations for the differentM. tuberculosis whiBfamily members. This information together with biochemical analyses of thewhiB1towhiB7gene products will be important for understanding the biology of this novel family of proteins in mycobacteria and related actinomycetes.
Resistance Levels and
rpoB
Gene Mutations among In Vitro-Selected Rifampin-Resistant
Mycobacterium tuberculosis
Mutants
Authors: Huitric Emma , Werngren Jim , Juréen Pontus , Hoffner Sven 
Published: July 2006

ABSTRACT

The distribution and resistance levels of 189 in vitro-selected rifampin-resistant
Mycobacterium tuberculosis
mutants of Beijing and other genotypes were determined. Apart from a higher amount of codon 522 point mutations and large deletions, a spread of mutations similar to that reported for clinical isolates was seen. Most mutations were correlated with high-level resistance; a lower level, or a MIC of <16 mg/liter, was associated with codon 522 mutations. Multiple mutations were detected in two Beijing mutants.
Candida albicans
and
Candida glabrata
Clinical Isolates Exhibiting Reduced Echinocandin Susceptibility
Authors: Katiyar Santosh , Pfaller Michael , Edlind Thomas 
Published: July 2006

ABSTRACT

A recognized hotspot for mutations conferring reduced echinocandin susceptibility (RES) is residue S645 of
Candida albicans
Gsc1(Fks1). We report that the mutation F641Y is associated with RES in a
C. albicans
isolate. The analogous Fks2 residue is mutated F to V in a
Candida glabrata
RES isolate; the introduction of this mutation into susceptible
C. glabrata
confirmed its role in RES. Y641-equivalent Fks residues were identified in intrinsically RES
Fusarium
species and
Candida guilliermondii
.
Fosmidomycin plus Clindamycin for Treatment of Pediatric Patients Aged 1 to 14 Years with
Plasmodium falciparum
Malaria
Authors: Borrmann Steffen , Lundgren Ingrid , Oyakhirome Sunny , Impouma Bénido , Matsiegui Pierre-Blaise , Adegnika Ayola A. , Issifou Saadou , Kun Jürgen F. J. , Hutchinson David , Wiesner Jochen , Jomaa Hassan , Kremsner Peter G. 
Published: July 2006

ABSTRACT

Fosmidomycin plus clindamycin was shown to be efficacious in the treatment of uncomplicated
Plasmodium falciparum
malaria in a small cohort of pediatric patients aged 7 to 14 years, but more data, including data on younger children with less antiparasitic immunity, are needed to determine the potential value of this new antimalarial combination. We conducted a single-arm study to improve the precision of efficacy estimates for an oral 3-day fixed-ratio combination of fosmidomycin and clindamycin at 30 and 10 mg/kg of body weight, respectively, every 12 hours for the treatment of uncomplicated
P. falciparum
malaria in 51 pediatric outpatients aged 1 to 14 years. Fosmidomycin plus clindamycin was generally well tolerated, but relatively high rates of treatment-associated neutropenia (8/51 [16%]) and falls of hemoglobin concentrations of ≥2 g/dl (7/51 [14%]) are of concern. Asexual parasites and fever were cleared within median periods of 42 h and 38 h, respectively. All patients who could be evaluated were parasitologically and clinically cured by day 14 (49/49; 95% confidence interval [CI], 93 to 100%). The per-protocol, PCR-adjusted day 28 cure rate was 89% (42/47; 95% CI, 77 to 96%). Efficacy appeared to be significantly reduced in children aged 1 to 2 years, with a day 28 cure rate of only 62% for this small subgroup (5/8). The inadequate efficacy in children of <3 years highlights the need for continued systematic studies of the current dosing regimen, which should include randomized trial designs.
Combination Chemotherapy with the Nitroimidazopyran PA-824 and First-Line Drugs in a Murine Model of Tuberculosis
Authors: Nuermberger Eric , Rosenthal Ian , Tyagi Sandeep , Williams Kathy N. , Almeida Deepak , Peloquin Charles A. , Bishai William R. , Grosset Jacques H. 
Published: July 2006

ABSTRACT
The creation of new chemotherapeutic regimens that permit shortening the duration of treatment is a major priority for antituberculosis drug development. In this study, we used the murine model of experimental tuberculosis therapy to determine whether incorporation of the investigational new nitroimidazopyran PA-824 into the standard first-line regimen has the potential to shorten the 6-month duration of treatment. As demonstrated previously, PA-824 alone had significant bactericidal activity over the first 2 months of treatment. Moreover, the substitution of PA-824 for isoniazid led to significantly lower lung CFU counts after 2 months of treatment and to more rapid culture-negative conversion compared to the standard regimen of rifampin, isoniazid, and pyrazinamide. Despite this, there was no difference in the proportion of mice relapsing after completing 6 months of therapy (2 of 19 mice treated with PA-824 in place of isoniazid relapsed versus 0 of 46 mice treated with the standard regimen). Meanwhile, no other PA-824-containing regimen tested was superior to the standard regimen on any assessment. Thus, we were unable to establish a clear role for PA-824 in a treatment-shortening regimen that includes two or more of the current first-line drugs. Future preclinical studies should include the evaluation of novel combinations of PA-824 with new drug candidates in addition to existing antituberculosis drugs for their potential to substantially improve the treatment of both drug-susceptible and multidrug-resistant tuberculosis.
Killing Kinetics of Caspofungin, Micafungin, and Amphotericin B against
Candida guilliermondii
Authors: Cantón Emilia , Pemán Javier , Sastre Macrina , Romero Mónica , Espinel-Ingroff Ana 
Published: July 2006

ABSTRACT
Amphotericin B (AMB), micafungin, and caspofungin MICs, minimal fungicidal concentrations, and time-killing curves were determined in the presence and absence of 10% inactivated serum. AMB was the only agent with consistent killing activity (time required to achieve 99.9% of growth reduction was 2.1 to 3.2 h). The presence of serum enhanced caspofungin activity but lowered those of micafungin and AMB.
Dose Separation Does Not Overcome the Pharmacokinetic Interaction between Fosamprenavir and Lopinavir/Ritonavir
Authors: Corbett Amanda H. , Patterson Kristine B. , Tien Hsiao-Chuan , Kalvass Leslie A. , Eron Joseph J. , Ngo Linh T. , Lim Michael L. , Kashuba Angela D. M. 
Published: July 2006

ABSTRACTPrevious investigations have shown a significant negative two-way drug interaction between fosamprenavir (FPV) and lopinavir/ritonavir (LPV/RTV) in both human immunodeficiency virus (HIV)-infected patients and seronegative volunteers. This randomized, nonblinded, three-way crossover study of HIV-seronegative adult volunteers investigated dose separation and increased doses of RTV as a means to overcome the interaction between FPV and LPV/RTV. Eleven HIV-seronegative volunteers were given FPV plus LPV/RTV at 700 mg plus 400/100 mg every 12 hours (q12h) simultaneously for 10 days and then randomized to receive each of three 7-day treatments in one of six possible sequences, as follows: FPV plus LPV/RTV at 700 mg plus 400 mg/100 mg q12h simultaneously, FPV/RTV at 700 mg/100 mg q12h plus LPV/RTV at 400 mg/100 mg q12h, with doses separated by 4 h, and FPV/RTV at 1,400 mg/200 mg in the morning plus LPV/RTV at 800 mg/200 mg in the evening. Pharmacokinetic sampling was performed on day 8 of each treatment, and samples were analyzed for FPV, amprenavir (APV), LPV, and RTV concentrations by high-performance liquid chromatography-tandem mass spectrometry. Geometric mean ratios (GMR [with 95% confidence intervals]) for the 4- and 12-h dose separation strategies compared to simultaneous administration were calculated for the areas under the concentration-time curves from 0 to 24 h. Compared to simultaneous administration, RTV exposures increased with both 4-h and 12-h dose separation strategies (GMR, 5.30 [3.66 to 7.67] and 4.45 [3.09 to 6.41], respectively). LPV exposures also significantly increased with both 4-h and 12-h dose separation strategies (GMR, 1.76 [1.34 to 2.32] and 1.43 [1.02 to 2.01], respectively). However, both the 4- and 12-h strategies resulted in greater reductions in APV exposure (0.67 [0.54 to 0.83] and 0.77 [0.59 to 0.99], respectively) compared to simultaneous administration. Additional investigations are warranted to determine the optimal dosing of FPV with LPV/RTV.
Alkoxyalkyl Esters of (
S
)-9-[3-Hydroxy-2-(Phosphonomethoxy)Propyl]Adenine Are Potent Inhibitors of the Replication of Wild-Type and Drug-Resistant Human Immunodeficiency Virus Type 1 In Vitro
Authors: Hostetler Karl Y. , Aldern Kathy A. , Wan William B. , Ciesla Stephanie L. , Beadle James R. 
Published: July 2006

ABSTRACT

(
S
)-9-[3-Hydroxy-2-(phosphonomethoxy)propyl]adenine [(
S
)-HPMPA], is an effective broad-spectrum antiviral against many DNA viruses but has been reported to be inactive against human immunodeficiency virus (HIV). We synthesized several alkoxyalkyl esters of (
S
)-HPMPA and now report that hexadecyloxypropyl-(
S
)-HPMPA [HDP-(
S
)-HPMPA] and octadecyloxyethyl-(
S
)-HPMPA [ODE-(
S
)-HPMPA]had 50% effective concentrations of 0.4 to 7.0 nanomolar and were nearly fully active against HIV variants having reverse transcriptase mutations M184V and K103N and against a zidovudine-resistant variant with mutations D67N, K70R, T215Y, and K219Q. Resistance to HDP-(
S
)-HPMPA and ODE-(
S
)-HPMPA was noted for a mutant with mutation K65R. HDP-(
S
)-HPMPA is also active against herpes simplex virus type 1, human cytomegalovirus, hepatitis B virus, adenoviruses, and orthopoxviruses and is worthy of further evaluation as a possibly therapy for HIV infection.
Outer Membrane Protein Changes and Efflux Pump Expression Together May Confer Resistance to Ertapenem in
Enterobacter cloacae
Authors: Szabó Dóra , Silveira Fernanda , Hujer Andrea M. , Bonomo Robert A. , Hujer Kristine M. , Marsh Jane W. , Bethel Christopher R. , Doi Yohei , Deeley Kathleen , Paterson David L. 
Published: July 2006

ABSTRACT

We investigated ertapenem-susceptible and -resistant extended-spectrum β-lactamase-producing
Enterobacter cloacae
isolates obtained from the same patient. Gene transcription of OmpD and OmpF was diminished in the ertapenem-resistant isolate. An efflux pump inhibitor decreased the MICs of ertapenem in the resistant strain, suggesting a potential role of efflux pumps in ertapenem resistance.
Model for Intracellular Lamivudine Metabolism in Peripheral Blood Mononuclear Cells Ex Vivo and in Human Immunodeficiency Virus Type 1-Infected Adolescents
Authors: Zhou Zexun , Rodman John H. , Flynn Patricia M. , Robbins Brian L. , Wilcox Carrie K. , D'Argenio David Z. 
Published: July 2006

ABSTRACT
The pharmacologic variability of nucleoside reverse transcriptase inhibitors such as lamivudine (3TC) includes not only systemic pharmacokinetic variability but also interindividual differences in cellular transport and metabolism. A modeling strategy linking laboratory studies of intracellular 3TC disposition with clinical studies in adolescent patients is described. Data from ex vivo laboratory experiments using peripheral blood mononuclear cells (PBMCs) from uninfected human subjects were first used to determine a model and population parameter estimates for 3TC cellular metabolism. Clinical study data from human immunodeficiency virus type 1-infected adolescents were then used in a Bayesian population analysis, together with the prior information from the ex vivo analysis, to develop a population model for 3TC systemic kinetics and cellular kinetics in PBMCs from patients during chronic therapy. The laboratory results demonstrate that the phosphorylation of 3TC is saturable under clinically relevant concentrations, that there is a rapid equilibrium between 3TC monophosphate and diphosphate and between 3TC diphosphate and triphosphate, and that 3TC triphosphate is recycled to 3TC monophosphate through a 3TC metabolite that remains to be definitively characterized. The resulting population model shows substantial interindividual variability in the cellular kinetics of 3TC with population coefficients of variation for model parameters ranging from 47 to 87%. This two-step ex vivo/clinical modeling approach using Bayesian population modeling of 3TC that links laboratory and clinical data has potential application for other drugs whose intracellular pharmacology is a major determinant of activity and/or toxicity.
qnr
Prevalence in Ceftazidime-Resistant
Enterobacteriaceae
Isolates from the United States
Authors: Robicsek A. , Strahilevitz J. , Sahm D. F. , Jacoby G. A. , Hooper D. C. 
Published: July 2006

ABSTRACT

We screened 313 ceftazidime-resistant
Enterobacteriaceae
isolates obtained in the United States from 1999 to 2004 for all three known
qnr
genes. A
qnr
gene was present in 20% of
Klebsiella pneumoniae
isolates, 31% of
Enterobacter
sp. isolates, and 4% of
Escherichia coli
isolates.
qnrA
and
qnrB
occurred with equivalent frequencies and, except for
qnrB
in enterobacters, were stable over time.
qnrS
was absent.
Sensitivity of Radiative–Convective Equilibrium Simulations to Horizontal Resolution
Authors: Pauluis Olivier , Garner Stephen 
Published: July 2006

Abstract
This paper investigates the impacts of horizontal resolution on the statistical behavior of convection. An idealized radiative–convective equilibrium is simulated for model resolutions ranging between 2 and 50 km. The simulations are compared based upon the analysis of the mean state, the energy and water vapor transport, and the probability distribution functions for various quantities. It is shown that, at a coarse resolution, the model is unable to capture the mixing associated with shallow clouds. This results in a dry bias in the lower troposphere, and in an excessive amount of water clouds. Despite this deficiency, the coarse resolution simulations are able to reproduce reasonably well the statistical properties of deep convective towers. This is particularly apparent in the cloud ice and vertical velocity distributions that exhibit a very robust behavior.
A theoretical scaling for the vertical velocity as function of the grid resolution is derived based upon the behavior of an idealized air bubble. It is shown that the vertical velocity of an ascending air parcel is determined by its aspect ratio, with a wide, flat parcel rising at a much slower pace than a narrow one. This theoretical scaling law exhibits a similar sensitivity to that of the numerical simulations. It is used to renormalize the probability distribution functions for vertical velocity, which show a very good agreement for resolutions up to 16 km. This new scaling law offers a way to improve direct simulations of deep convection in coarse resolution models.