bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanism of Active Renal Tubular Efflux of Tenofovir
Authors: Ray Adrian S. , Cihlar Tomas , Robinson Kelly L. , Tong Leah , Vela Jennifer E. , Fuller Michael D. , Wieman Lani M. , Eisenberg Eugene J. , Rhodes Gerry R. 
Published: September 2006

ABSTRACTTenofovir (TFV) undergoes renal elimination by a combination of glomerular filtration and active tubular secretion. While transporter-mediated uptake of TFV from the blood into proximal-tubule cells has been well characterized, comparatively little is known about the efflux system responsible for transporting TFV into the lumen during active tubular secretion. Therefore, members of the ATP-binding cassette family of efflux pumps expressed at the apical side of proximal-tubule cells were studied for the ability to transport TFV. Studies in multiple independent in vitro systems show TFV not to be a substrate for P glycoprotein (Pgp) or multidrug resistance protein type 2 (MRP2). In contrast to Pgp and MRP2, TFV was observed to be a substrate for MRP4. TFV accumulated to fivefold lower levels in MRP4-overexpressing cells, and its accumulation could be increased by an MRP inhibitor. Furthermore, MRP4-overexpressing cells were found to be 2.0- to 2.5-fold less susceptible to cytotoxicity caused by TFV. ATP-dependent uptake of TFV was observed in membrane vesicles containing MRP4 but not in vesicles lacking the transporter. On the basis of these and previous results, the molecular transport pathway for the active tubular secretion of TFV through renal proximal-tubule cells involves uptake from the blood mediated by human organic anion transporters 1 and 3 and efflux into urine by MRP4. A detailed understanding of the molecular mechanism of TFV active tubular secretion will facilitate the assessment of potential renal drug-drug interactions with coadministered agents.
High-Level Carbapenem Resistance in a
Klebsiella pneumoniae
Clinical Isolate Is Due to the Combination of
bla
ACT-1
β-Lactamase Production, Porin OmpK35/36 Insertional Inactivation, and Down-Regulation of the Phosphate Transport Porin PhoE
Authors: Kaczmarek Frank M. , Dib-Hajj Fadia , Shang Wenchi , Gootz Thomas D. 
Published: September 2006

ABSTRACT

Clinical isolates of
Klebsiella pneumoniae
resistant to carbapenems and essentially all other antibiotics (multidrug resistant) are being isolated from some hospitals in New York City with increasing frequency. A highly related pair of
K. pneumoniae
strains isolated on the same day from one patient in a hospital in New York City were studied for antibiotic resistance. One (KP-2) was resistant to imipenem, meropenem, and sulopenem (MICs of 16 to 32 μg/ml) while the other (KP-1) was susceptible (MIC of 0.5 μg/ml); both contained the
bla
ACT-1
,
bla
SHV-1
, and
bla
TEM-1
β-lactamases.
bla
ACT-1
in both strains was encoded on a large ∼150-kb plasmid. Both isolates contained an identical class 1 integron encoding resistance to aminoglycosides and chloramphenicol. They each had identical insertions in
ompK35
and
ompK36
, resulting in disruption of these key porin genes. The carbapenem-resistant and -susceptible isolates were extensively studied for differences in the structural and regulatory genes for the operons
acrRAB
,
marORAB
,
romA-ramA
,
soxRS
,
micF
,
micC
,
phoE
,
phoBR
,
rpoS
, and
hfq
. No changes were detected between the isolates except for a significant down-regulation of
ompK37
,
phoB
, and
phoE
in KP-2 as deduced from reverse transcription-PCR analysis of mRNA and polyacrylamide gel electrophoresis separation of outer membrane proteins. Backcross analysis was conducted using the wild-type
phoE
gene cloned into the vector pGEM under regulation of its native promoter as well as the
lacZ
promoter following transformation into the resistant KP-2 isolate. The wild-type gene reversed carbapenem resistance only when under control of the heterologous
lacZ
promoter. In the background of
ompK35-ompK36
gene disruption, the up-regulation of
phoE
in KP-1 apparently compensated for porin loss and conferred carbapenem susceptibility. Down-regulation of
phoE
in KP-2 may represent the normal state of this gene, or it may have been selected from KP-1 in vivo under antibiotic pressure, generating the carbapenem-resistant clone. This is the first study in the
Enterobacteriaceae
where expression of the phosphate-regulated PhoE porin has been associated with resistance to antimicrobials. Our results with this pair of
Klebsiella
clinical isolates highlight the complex and evolving nature of multiple drug resistance in this species.
Role of VraSR in Antibiotic Resistance and Antibiotic-Induced Stress Response in
Staphylococcus aureus
Authors: Gardete S. , Wu S. W. , Gill S. , Tomasz A. 
Published: September 2006

ABSTRACT

Exposure of
Staphylococcus aureus
to cell wall inhibitors induces massive overexpression of a number of genes, provided that the VraSR two-component sensory regulatory system is intact. Inactivation of
vraS
blocks this transcriptional response and also causes a drastic reduction in the levels of resistance to beta-lactam antibiotics and vancomycin. We used an experimental system in which the essential cell wall synthesis gene of
S. aureus
,
pbpB
, was put under the control of an isopropyl-β-
d
-thiogalactopyranoside-inducible promoter in order to induce reversible perturbations in cell wall synthesis without the use of any cell wall-active inhibitor. Changes in the level of transcription of
pbpB
were rapidly followed by parallel changes in the
vraSR
signal, and the abundance of the
pbpB
transcript was precisely mirrored by the abundance of the transcripts of
vraSR
and some additional genes that belong to the VraSR regulon. Beta-lactam resistance in
S. aureus
appears to involve a complex stress response in which VraSR performs the critical role of a sentinel system capable of sensing the perturbation of cell wall synthesis and allowing mobilization of genes that are essential for the generation of a highly resistant phenotype. One of the sites in cell wall synthesis “sensed” by the VraSR system appears to be a step catalyzed by PBP 2.
SME-3, a Novel Member of the
Serratia marcescens
SME Family of Carbapenem-Hydrolyzing β-Lactamases
Authors: Queenan Anne Marie , Shang Wenchi , Schreckenberger Paul , Lolans Karen , Bush Karen , Quinn John 
Published: September 2006

ABSTRACT

Imipenem-resistant
Serratia marcescens
isolates were cultured from a lung transplant patient given multiple antibiotics over several months. The strains expressed SME-3, a β-lactamase of the rare SME carbapenem-hydrolyzing family. SME-3 differed from SME-1 by a single amino acid substitution of tyrosine for histidine at position 105, but the two β-lactamases displayed similar hydrolytic profiles.
Ribavirin Antagonizes the In Vitro Anti-Hepatitis C Virus Activity of 2′-
C
-Methylcytidine, the Active Component of Valopicitabine
Authors: Coelmont Lotte , Paeshuyse Jan , Windisch Marc P. , De Clercq Erik , Bartenschlager Ralf , Neyts Johan 
Published: September 2006

ABSTRACT

Ribavirin antagonizes the in vitro anti-hepatitis C virus (HCV) activity of the pyrimidine nucleoside analogue 2′-
C
-methylcytidine, the active component of the experimental anti-HCV drug valopicitabine. In contrast, the combination of ribavirin with either the purine nucleoside analogue 2′-
C
-methyladenosine or the HCV protease inhibitor VX-950 resulted in an additive antiviral activity. These findings may have implications when planning clinical studies with valopicitabine.
Effect of Tigecycline on Normal Oropharyngeal and Intestinal Microflora
Authors: Nord Carl Erik , Sillerström Eva , Wahlund Elisabeth 
Published: September 2006

ABSTRACT

Antibacterial agents disrupt the ecological balance of the normal human microflora. Tigecycline, a member of a new class of antibiotics (glycylcyclines), has been shown to have a potent broad-spectrum activity against most gram-positive and gram-negative aerobic and anaerobic bacteria. The aim of the study was to investigate the ecological effects of tigecycline on the normal oropharyngeal and intestinal microflora of healthy subjects. Thirteen healthy white subjects (six females and seven males) between 20 and 31 years of age received 100 mg of tigecycline in the morning on day 1 as a 30-min intravenous infusion followed by a 50-mg dose of tigecycline every 12 h as a 30-minute infusion for 10 days. One subject was withdrawn on day 2 because of an adverse event (urticaria). Serum, saliva, and fecal samples were collected before, during, and after administration for microbiological cultivation and for assays of tigecycline. All new colonizing bacteria were tested for susceptibility (resistance of ≥8 mg/liter) during the investigation period. The fecal concentrations on day 8 were from 3.0 to 14.1 mg/kg, with a mean value of 6.0 mg/kg and a median value of 5.6 mg/kg. The saliva concentrations were generally low (0 to 0.12 mg/liter). A minor effect on the oropharyngeal microflora was observed. The numbers of enterococci and
Escherichia coli
cells in the intestinal microflora were reduced at day 8 (
P
< 0.05), while those of other enterobacteria and yeasts increased. There was a marked reduction of lactobacilli and bifidobacteria (
P
< 0.05) but no impact on bacteroides. No
Clostridium difficile
strains were isolated. Two
Klebsiella pneumoniae
strains and five
Enterobacter cloacae
strains resistant to tigecycline were found on day 8.
Novel Robust Hepatitis C Virus Mouse Efficacy Model
Authors: Zhu Qing , Oei Yoko , Mendel Dirk B. , Garrett Evelyn N. , Patawaran Montesa B. , Hollenbach Paul W. , Aukerman Sharon L. , Weiner Amy J. 
Published: September 2006

ABSTRACTThe lack of a robust small-animal model for hepatitis C virus (HCV) has hindered the discovery and development of novel drug treatments for HCV infections. We developed a reproducible and easily accessible xenograft mouse efficacy model in which HCV RNA replication is accurately monitored in vivo by real-time, noninvasive whole-body imaging of gamma-irradiated SCID mice implanted with a mouse-adapted luciferase replicon-containing Huh-7 cell line (T7-11). The model was validated by demonstrating that both a small-molecule NS3/4A protease inhibitor (BILN 2061) and human alpha interferon (IFN-α) decreased HCV RNA replication and that treatment withdrawal resulted in a rebound in replication, which paralleled clinical outcomes in humans. We further showed that protease inhibitor and IFN-α combination therapy was more effective in reducing HCV RNA replication than treatment with each compound alone and supports testing in humans. This robust mouse efficacy model provides a powerful tool for rapid evaluation of potential anti-HCV compounds in vivo as part of aggressive drug discovery efforts.
Method for Regulated Expression of Single-Copy Efflux Pump Genes in a Surrogate
Pseudomonas aeruginosa
Strain: Identification of the BpeEF-OprC Chloramphenicol and Trimethoprim Efflux Pump of
Burkholderia pseudomallei
1026b
Authors: Kumar Ayush , Chua Kim-Lee , Schweizer Herbert P. 
Published: September 2006

ABSTRACT

Construction and integration of recombinant mini-Tn
7
expression vectors into the chromosome of a surrogate, efflux-sensitized, and biosafe
Pseudomonas aeruginosa
host was validated as a generally applicable method for studies of uncharacterized bacterial efflux pumps. Using this method, the
Burkholderia pseudomallei bpeEF-oprC
operon was shown to encode a chloramphenicol and trimethoprim efflux pump.
Effect of Rifampin on Steady-State Pharmacokinetics of Atazanavir with Ritonavir in Healthy Volunteers
Authors: Burger D. M. , Agarwala S. , Child M. , Been-Tiktak A. , Wang Y. , Bertz R. 
Published: September 2006

ABSTRACTMycobacterium tuberculosisis a concern in patients with human immunodeficiency virus (HIV) infection. Rifampin (RIF), an agent used againstM. tuberculosis, is contraindicated with most HIV protease inhibitors. Atazanavir (ATV) has clinical efficacy comparable to a standard of care regimen in naive patients and, when dosed with low-dose ritonavir (RTV), also in treatment-experienced patients. We evaluated here the safety and pharmacokinetics of ATV, resulting from three regimens of ATV, RTV, and RIF in 71 healthy subjects. The pharmacokinetics for ATV and RTV were assessed after 6 and 10 days of dosing with ATV 400 mg (n= 53) and with ATV-RTV at 300 and 100 mg (ATV/RTV 300/100;n= 52), respectively. Steady-state pharmacokinetics for ATV, RTV, RIF, and desacetyl-rifampin (des-RIF) were measured after 10 days of dosing of ATV/RTV/RIF 300/100/600 (n= 17), ATV/RTV/RIF 300/200/600 (n= 17), or ATV/RTV/RIF 400/200/600 (n= 14). An RIF 600-alone arm was enrolled as a control group (n= 18). With ATV/RTV/RIF 400/200/600, ATV area under the concentration-time curve values were comparable, but theCminvalues were lower relative to ATV 400 alone. ATV exposures were substantially reduced for the other RIF-containing regimens relative to ATV 400 alone and for all regimens relative to ATV/RTV 300/100 alone. RIF and des-RIF exposures were 1.6- to 2.5-fold higher than with RIF 600 alone. The incidence of grade 3/4 alanine aminotransferase/aspartate aminotransferase values was limited to 1 subject each in both the ATV/RTV/RIF 300/200/600 and the ATV/RTV/RIF 400/200/600 treatments. Coadministration of ATV with RIF was safe and generally well tolerated. Since ATV exposures were reduced in all regimens, ATV and RIF should not be coadministered at the dosing regimens studied.
Mycobacterium leprae
Is Naturally Resistant to PA-824
Authors: Manjunatha Ujjini H. , Lahiri Ramanuj , Randhawa Baljit , Dowd Cynthia S. , Krahenbuhl James L. , Barry Clifton E. 
Published: September 2006

ABSTRACT

Leprosy responds very slowly to the current multidrug therapy, and hence there is a need for novel drugs with potent bactericidal activity. PA-824 is a 4-nitroimidazo-oxazine that is currently undergoing phase I clinical trials for the treatment of tuberculosis. The activity of PA-824 against
Mycobacterium leprae
was tested and compared with that of rifampin in axenic cultures, macrophages, and two different animal models. Our results conclusively demonstrate that PA-824 has no effect on the viability of
M. leprae
in all three models, consistent with the lack of the nitroimidazo-oxazine-specific nitroreductase, encoded by Rv3547 in the
M. leprae
genome, which is essential for activation of this molecule.
Engineered VaginalLactobacillusStrain for Mucosal Delivery of the Human Immunodeficiency Virus Inhibitor Cyanovirin-N
Authors: Liu Xiaowen , Lagenaur Laurel A. , Simpson David A. , Essenmacher Kirsten P. , Frazier-Parker Courtney L. , Liu Yang , Tsai Daniel , Rao Srinivas S. , Hamer Dean H. , Parks Thomas P. , Lee Peter P. , Xu Qiang 
Published: September 2006

ABSTRACTWomen are at significant risk of human immunodeficiency virus (HIV) infection, with the cervicovaginal mucosa serving as a major portal for virus entry. Female-initiated preventatives, including topical microbicides, are urgently needed to help curtail the HIV/AIDS pandemic. Here we report on the development of a novel, live microbicide that employs a natural vaginal strain ofLactobacillus jenseniiengineered to deliver the potent HIV inhibitor cyanovirin-N (CV-N). To facilitate efficient expression of CV-N by this bacterium, theL. jensenii1153 genome was sequenced, allowing identification of native regulatory elements and sites for the chromosomal integration of heterologous genes. A CV-N expression cassette was optimized and shown to produce high levels of structurally intact CV-N when expressed inL. jensenii. Lactobacillus-derived CV-N was capable of inhibiting CCR5-tropic HIVBaLinfectivity in vitro with a 50% inhibitory concentration of 0.3 nM. The CV-N expression cassette was stably integrated as a single copy into the bacterial chromosome and resolved from extraneous plasmid DNA without adversely affecting the bacterial phenotype. This bacterial strain was capable of colonizing the vagina and producing full-length CV-N when administered intravaginally to mice during estrus phase. The CV-N-producingLactobacilluswas genetically stable when propagated in vitro and in vivo. This work represents a major step towards the development of an inexpensive yet durable protein-based microbicide to block the heterosexual transmission of HIV in women.
Ciprofloxacin-Resistant Gram-Negative Bacilli in the Fecal Microflora of Children
Authors: Qin Xuan , Razia Yasmin , Johnson James R. , Stapp Jennifer R. , Boster Daniel R. , Tsosie Treva , Smith Donna L. , Braden Christopher R. , Gay Kathryn , Angulo Frederick J. , Tarr Phillip I. 
Published: September 2006

ABSTRACT

The extent to which antibiotic-resistant bacteria are excreted by humans who have not been exposed to antibiotics is not known. Children, who rarely receive fluoroquinolones, provide opportunities to assess the frequency of fecal excretion by fluoroquinolone-naïve hosts of fluoroquinolone-resistant gram-negative bacilli. Fresh nondiarrheal stools from children were processed by screening them on agar containing ciprofloxacin to recover ciprofloxacin-resistant gram-negative bacilli. Resistant isolates were identified, and ciprofloxacin MICs were determined. Resistant
Escherichia coli
isolates were also analyzed for urovirulence-associated loci. Thirteen (2.9%) of 455 stools yielded ciprofloxacin-resistant
E. coli
(seven children),
Stenotrophomonas maltophilia
(four children), and
Achromobacter xylosoxidans
and
Enterobacter aerogenes
(one child each). Neither the subjects themselves nor members of their households used fluoroquinolones in the 4 weeks preceding collection. Six of the seven resistant
E. coli
isolates belonged to phylogenetic groups B2 and D, in which extraintestinal pathogenic
E. coli
bacteria are frequently found. All resistant
E. coli
isolates contained at least three putative
E. coli
virulence loci. Most ciprofloxacin-resistant bacteria were resistant to additional antibiotics. Potentially pathogenic bacteria that are resistant to therapeutically important antimicrobial agents are excreted by some humans, despite these persons' lack of exposure to the particular drugs. The sources of these resistant organisms are unknown. This underrecognized reservoir of drug-resistant potential pathogens poses public health challenges.
Efficacy of Ambruticin Analogs in a Murine Model of Invasive Pulmonary Aspergillosis
Authors: Chiang Lisa Y. , Ejzykowicz Daniele E. , Tian Zong-Qiang , Katz Leonard , Filler Scott G. 
Published: September 2006

ABSTRACT
Ambruticins are a family of polyketides. The antifungal activity of an ambruticin, KOSN-2079, was tested in the mouse model of invasive aspergillosis. KOSN-2079 significantly reduced pulmonary fungal burdens and improved survival over that with the vehicle control. These results support the continued development of ambruticins as antifungal agents.
Protein
O-
Mannosyltransferase Isoforms Regulate Biofilm Formation in
Candida albicans
Authors: Peltroche-Llacsahuanga Heidrun , Goyard Sophie , d′Enfert Christophe , Prill Stephan K.-H. , Ernst Joachim F. 
Published: September 2006

ABSTRACT

Five isoforms of protein mannosyltransferase (Pmt)
O
-mannosylate secretory proteins in
Candida albicans. pmt
mutants were differentially defective for biofilm formation on plastic in static and flow-through systems, and a Pmt inhibitor blocked early stages of biofilm formation. Conceptually, Pmt inhibition may prevent surface anchoring and biofilm-dependent resistance of fungal pathogens.
Redefining a Structural Variant of Staphylococcal Cassette Chromosome
mec
, SCC
mec
Type VI
Authors: Oliveira Duarte C. , Milheiriço Catarina , de Lencastre Hermínia 
Published: September 2006

ABSTRACT

Previously we identified a SCC
mec
variant similar in size to type IV but with a new
ccrAB
allotype, allotype 4. We addressed the epidemiological relevance of this variant and found it among several strains belonging to the same clone. We propose to rename this structural variant SCC
mec
type VI.
Efficacy of Ambruticin Analogs in a Murine Model of Coccidioidomycosis
Authors: Shubitz Lisa F. , Galgiani John N. , Tian Zong-Qiang , Zhong Ziyang , Timmermans Pieter , Katz Leonard 
Published: September 2006

ABSTRACT

Ambruticin S, an antifungal cyclopropyl-pyran acid, showed curative effects against murine coccidioidal infection. Two analogs of this compound with greater in vitro potency were tested against lethal murine
Coccidioides
infection. Both improved the survival of mice over that of controls; one resulted in near-sterilization of infection.
Potent Antiviral Synergy between Monoclonal Antibody and Small-Molecule CCR5 Inhibitors of Human Immunodeficiency Virus Type 1
Authors: Murga Jose D. , Franti Michael , Pevear Daniel C. , Maddon Paul J. , Olson William C. 
Published: September 2006

ABSTRACTThe chemokine receptor CCR5 provides a portal of entry for human immunodeficiency virus type 1 (HIV-1) into susceptible CD4+cells. Both monoclonal antibody (MAb) and small-molecule CCR5 inhibitors have entered human clinical testing, but little is known regarding their potential interactions. We evaluated the interactions between CCR5 MAbs, small-molecule CCR5 antagonists, and inhibitors of HIV-1 gp120, gp41, and reverse transcriptase in vitro. Inhibition data were analyzed for cooperative effects using the combination index (CI) method and stringent statistical criteria. Potent, statistically significant antiviral synergy was observed between the CCR5 MAb PRO 140 and the small-molecule CCR5 antagonists maraviroc (UK-427,857), vicriviroc (SCH-D), and TAK-779. High-level synergy was observed consistently across various assay systems, HIV-1 envelopes, CCR5 target cells, and inhibition levels. CI values ranged from 0.18 to 0.64 and translated into in vitro dose reductions of up to 14-fold. Competition binding studies revealed nonreciprocal patterns of CCR5 binding by MAb and small-molecule CCR5 inhibitors, suggesting that synergy occurs at the level of receptor binding. In addition, both PRO 140 and maraviroc synergized with the chemokine RANTES, a natural ligand for CCR5; however, additive effects were observed for both small-molecule CCR5 antagonists and PRO 140 in combination with other classes of HIV-1 inhibitors. The findings provide a rationale for clinical exploration of MAb and small-molecule CCR5 inhibitors in novel dual-CCR5 regimens for HIV-1 therapy.
Role of P Glycoprotein in Absorption of Novel Antimalarial Drugs
Authors: Crowe Andrew , Ilett Kenneth F. , Karunajeewa Harin A. , Batty Kevin T. , Davis Timothy M. E. 
Published: September 2006

ABSTRACT
Bidirectional transport of four novel antimalarial compounds was determined using Caco-2 cell monolayers. P glycoprotein-mediated efflux was greatest for pyronaridine (5 to 20 μM) and low for naphthoquine (5 μM). With 20 μM naphthoquine, net efflux was blocked, suggesting saturation of the transporter. Piperaquine and dihydroartemisinin were not transported by the system.