bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prevention and Cure of Systemic
Escherichia coli
K1 Infection by Modification of the Bacterial Phenotype
Authors: Mushtaq Naseem , Redpath Maria B. , Luzio J. Paul , Taylor Peter W. 
Published: April 2004

ABSTRACT

Escherichia coli
is a common cause of meningitis and sepsis in the newborn infant, and the large majority of isolates from these infections produce a polysialic acid (PSA) capsular polysaccharide, the K1 antigen, that protects the bacterial cell from immune attack. We determined whether a capsule-depolymerizing enzyme, by removing this protective barrier, could alter the outcome of systemic infection in an animal model. Bacteriophage-derived endosialidase E (endoE) selectively degrades the PSA capsule on the surface of
E. coli
K1 strains. Intraperitoneal administration of small quantities of recombinant endoE (20 μg) to 3-day-old rats, colonized with a virulent strain of K1, prevented bacteremia and death from systemic infection. The enzyme had no effect on the viability of
E. coli
strains but sensitized strains expressing PSA to killing by the complement system. This study demonstrates the potential therapeutic efficacy of agents that cure infections by modification of the bacterial phenotype rather than by killing or inhibition of growth of the pathogen.
Identification and Characterization of Inhibitors of Bacterial Enoyl-Acyl Carrier Protein Reductase
Authors: Ling Losee L. , Xian Jun , Ali Syed , Geng Bolin , Fan Jun , Mills Debra M. , Arvanites Anthony C. , Orgueira Hernan , Ashwell Mark A. , Carmel Gilles , Xiang Yibin , Moir Donald T. 
Published: April 2004

ABSTRACT

Bacterial enoyl-acyl carrier protein reductase (ENR) catalyzes an essential step in fatty acid biosynthesis. ENR is an attractive target for narrow-spectrum antibacterial drug discovery because of its essential role in metabolism and its sequence conservation across many bacterial species. In addition, the bacterial ENR sequence and structural organization are distinctly different from those of mammalian fatty acid biosynthesis enzymes. High-throughput screening to identify inhibitors of
Escherichia coli
ENR yielded four structurally distinct classes of hits. Several members of one of these, the 2-(alkylthio)-4,6-diphenylpyridine-3-carbonitriles (“thiopyridines”), inhibited both purified ENR (50% inhibitory concentration [IC
50
] = 3 to 25 μM) and the growth of
Staphylococcus aureus
and
Bacillus subtilis
(MIC = 1 to 64 μg/ml). The effect on cell growth is due in part to inhibition of fatty acid biosynthesis as judged by inhibition of incorporation of [
14
C]acetate into fatty acids and by the increased sensitivity of cells that underexpress an ENR-encoding gene (four- to eightfold MIC shift). Synthesis of a variety of compounds in this chemical series revealed a correlation between IC
50
and MIC, and the results provided initial structure-activity relationships. Preliminary structure-activity relationships, potency on purified ENR, and activity on bacterial cells indicate that members of the thiopyridine chemical series are effective fatty acid biosynthesis inhibitors suitable for further antibacterial development.
Pharmacokinetics of Adjusted-Dose Lopinavir-Ritonavir Combined with Rifampin in Healthy Volunteers
Authors: la Porte C. J. L. , Colbers E. P. H. , Bertz R. , Voncken D. S. , Wikstrom K. , Boeree M. J. , Koopmans P. P. , Hekster Y. A. , Burger D. M. 
Published: April 2004

ABSTRACT

Coadministration of lopinavir-ritonavir, an antiretroviral protease inhibitor, at the standard dose (400/100 mg twice a day [BID]) with the antituberculous agent rifampin is contraindicated because of a significant pharmacokinetic interaction due to induction of cytochrome P450 3A by rifampin. In the present study, two adjusted-dose regimens of lopinavir-ritonavir were tested in combination with rifampin. Thirty-two healthy subjects participated in a randomized, two-arm, open-label, multiple-dose, within-subject controlled study. All subjects were treated with lopinavir-ritonavir at 400/100 mg BID from days 1 to 15. From days 16 to 24, the subjects in arm 1 received lopinavir-ritonavir at 800/200 mg BID in a dose titration, and the subjects in arm 2 received lopinavir-ritonavir at 400/400 mg BID in a dose titration. Rifampin was given at 600 mg once daily to all subjects from days 11 to 24. The multiple-dose pharmacokinetics of lopinavir, ritonavir, and rifampin were assessed. Twelve of 32 subjects withdrew from the study. For nine subjects lopinavir-ritonavir combined with rifampin resulted in liver enzyme level elevations. Pharmacokinetic data for 19 subjects were evaluable. Geometric mean ratios for the lopinavir minimum concentration in serum and the maximum concentration in serum (
C
max
) on day 24 versus that on day 10 were 0.43 (90% confidence interval [CI], 0.19 to 0.96) and 1.02 (90% CI, 0.85 to 1.23), respectively, for arm 1 (
n
= 10) and 1.03 (90% CI, 0.68 to 1.56) and 0.93 (90% CI, 0.81 to 1.07), respectively, for arm 2 (
n
= 9). Ritonavir exposure increased from days 10 to 24 in both arms. The geometric mean
C
max
of rifampin was 13.5 mg/liter (day 24) and was similar between the two arms. Adjusted-dose regimens of lopinavir-ritonavir in combination with therapeutic drug monitoring and monitoring of liver function may allow concomitant use of rifampin.
In Vitro Antifungal Activities of Inhibitors of Phospholipases from the Fungal Pathogen
Cryptococcus neoformans
Authors: Ganendren Ranjini , Widmer Fred , Singhal Vatsala , Wilson Christabel , Sorrell Tania , Wright Lesley 
Published: April 2004

ABSTRACT

Secreted phospholipase B is a proven virulence factor for the pathogenic fungus
Cryptococcus neoformans
and exhibits three phospholipase activities in the one protein. These are phospholipase B (PLB), lysophospholipase (LPL), and lysophospholipase transacylase (LPTA). Our aim was to investigate the feasibility of using this enzyme as a target for antifungal therapy. We determined in
C. neoformans
var.
grubii
strain H99 that 82% of PLB activity was secreted but that 64% of LPL activity and 70% of LPTA activity were cell associated. Cell-associated activities (cytosolic and membrane) were further characterized, since it is likely that any fungicidal effect would depend on inhibition of these enzymes. Four commercially available compounds with structural similarities to phospholipid substrates were tested as inhibitors. These were alexidine dihydrochloride (compound A), dioctadecyldimethylammonium bromide (compound O), 1,12 bis-(tributylphosphonium)dodecane dibromide (compound P), and decamethonium dibromide (compound D). The best phospholipase inhibitors (compounds A and P) were also the most potent antifungal agents by the standard broth microdilution test. Compound A was highly selective for secreted and cell-associated PLB activities and showed no inhibition of mammalian phospholipase
A
2
at 0.25 μM. Compound O, which was specific for secretory and cytosolic LPL and LPTA and membrane-associated PLB, was not antifungal. We conclude that inhibitors of cryptococcal phospholipases can be selective for fungal enzymes and intrinsically antifungal. They also provide tools for assessing the relative importance of the various enzyme activities in virulence. Our results enable further rational structure-function studies to validate the use of phospholipases as antifungal targets.
Biophysical Characterization of Endotoxin Inactivation by NK-2, an Antimicrobial Peptide Derived from Mammalian NK-Lysin
Authors: Andrä Jörg , Koch Michel H. J. , Bartels Rainer , Brandenburg Klaus 
Published: April 2004

ABSTRACT

NK-2, a membrane-acting antimicrobial peptide, was derived from the cationic core region of porcine NK-lysin and consists of 27 amino acid residues. It adopts an amphipathic, α-helical secondary structure and has been shown to interact specifically with membranes of negatively charged lipids. We therefore investigated the interaction of NK-2 with lipopolysaccharide (LPS), the main, highly anionic component of the outer leaflet of the outer membrane of gram-negative bacteria, by means of biophysical and biological assays. As model organisms and a source of LPS, we used
Salmonella enterica
strains with various lengths of the LPS carbohydrate moiety, including smooth LPS, rough LPS, and deep rough LPS (LPS Re) mutant strains. NK-2 binds to LPS Re with a high affinity and induces a change in the endotoxin-lipid A aggregate structure from a cubic or unilamellar structure to a multilamellar one. This structural change, in concert with a significant overcompensation of the negative charges of LPS, is thought to result in the neutralization of the endotoxic LPS activity in a cell culture system. Neutralization of LPS activity by NK-2 as well as its antibacterial activity against the various
Salmonella
strains strongly depends on the length of the sugar chains of LPS, with LPS Re being the most sensitive. This suggests that a hydrophobic peptide-LPS interaction is necessary for efficient neutralization of the biological activity of LPS and that the long carbohydrate chains, besides their function as a barrier for hydrophobic drugs, also serve as a trap for polycationic substances.
Feasibility of Radioimmunotherapy of Experimental Pneumococcal Infection
Authors: Dadachova E. , Burns T. , Bryan R. A. , Apostolidis C. , Brechbiel M. W. , Nosanchuk J. D. , Casadevall A. , Pirofski L. 
Published: April 2004

ABSTRACT

Streptococcus pneumoniae
is an important cause of community-acquired pneumonia, meningitis, and bacteremia. The problem of pneumococcal disease is exacerbated by increasing drug resistance. Furthermore, patients with impaired immunity are at high risk for invasive pneumococcal infections. Thus, there is an urgent need for new approaches to antimicrobial therapy. Antibody therapies take advantage of the specificity and high affinity of the antigen-antibody interaction to deliver antibacterial compounds to a site of infection in the form of naked or conjugated antibodies. We have recently established that radioimmunotherapy (RIT) can be used to treat experimental fungal infections in mice. In the present study, we investigated the feasibility of applying a RIT approach to the treatment of
S. pneumoniae
infection by evaluating the susceptibility of
S. pneumoniae
to radiolabeled antibody in vitro and in an animal infection model. For the specific antibody carrier, we used human monoclonal antibody D11, which binds to pneumococcal capsular polysaccharide 8. We have selected the alpha particle emitter
213
Bi as the radionuclide for conjugation to the antibody. Incubation of serotype 8
S. pneumoniae
with
213
Bi-D11 resulted in dose-dependent killing of bacteria. RIT of
S. pneumoniae
infection in C57BL/6 mice showed that 60% more mice survived in the
213
Bi-D11-treated group (80 μCi) than in the untreated group (
P
< 0.01). The treatment did not cause hematological toxicity, as demonstrated by platelet counts. This feasibility study establishes that RIT can be applied to the treatment of bacterial infections.
Mechanism of Action of the Ribopyranoside Benzimidazole GW275175X against Human Cytomegalovirus
Authors: Underwood Mark R. , Ferris Robert G. , Selleseth Dean W. , Davis Michelle G. , Drach John C. , Townsend Leroy B. , Biron Karen K. , Boyd F. Leslie 
Published: April 2004

ABSTRACT

New human cytomegalovirus (HCMV) therapies with novel mechanisms of action are needed to treat drug-resistant HCMV that arises during therapy with currently approved agents. 2-Bromo-5,6-dichloro-1-β-
d
-ribofuranosyl-1
H
-benzimidazole (BDCRB) is an effective anti-HCMV agent with a novel mechanism of action, but problems with in vivo stability preclude clinical development. A
d
-ribopyranosyl derivative of BDCRB, GW275175X, displays similar antiviral activity without the in vivo stability problems. We present an initial description of the activity of GW275175X against HCMV, other herpesviruses, and selected nonherpesviruses. In addition, we show that it acts as a DNA maturation inhibitor like the parent compound, BDCRB, rather than via the mechanisms of action of 1263W94 or any anti-HCMV drugs approved for marketing. GW275175X is a promising candidate for clinical development as an anti-HCMV agent.
Rabbit Model of
Candida albicans
Biofilm Infection: Liposomal Amphotericin B Antifungal Lock Therapy
Authors: Schinabeck Matthew K. , Long Lisa A. , Hossain Mohammad A. , Chandra Jyotsna , Mukherjee Pranab K. , Mohamed Sotohy , Ghannoum Mahmoud A. 
Published: April 2004

ABSTRACT

Catheter-related infections due to
Candida albicans
biofilms are a leading cause of fungal nosocomial bloodstream infection. In this paper, we describe the development of a model of catheter-associated infection with
C. albicans
biofilms and show that antifungal lock therapy with liposomal amphotericin B is an effective treatment strategy for these infections. Silicone catheters surgically placed in New Zealand White rabbits were infected with
C. albicans
, and the rabbits were randomized into three groups: (i) untreated controls, (ii) liposomal amphotericin B lock, and (iii) fluconazole lock. Upon completion of therapy, blood cultures were obtained and the catheters were removed for quantitative culture and scanning electron microscopic analyses. Quantitative cultures revealed that catheters treated with liposomal amphotericin B yielded 0 CFU, which was significant compared to the untreated controls (
P
< 0.001) and the fluconazole-treated group (
P
= 0.0079). Although fluconazole treatment tended to have lower CFU compared to untreated controls, there was no difference in mean colony counts between these two groups (1.128 ± 0.764 and 1.841 ± 1.141 log
10
CFU/catheter segment, respectively;
P
= 0.297). Scanning electron microscopy revealed abundant biofilm in the control and fluconazole groups, while the liposomal amphotericin B group was virtually cleared. These findings suggest a possible treatment strategy for the successful salvage of catheters infected with
C. albicans
biofilms and describe an animal model that may play an important role in the further study of
C. albicans
biofilm pathogenesis and evaluation of potential antibiofilm agents.
Trypanocidal Activity of Melamine-Based Nitroheterocycles
Authors: Stewart Mhairi L. , Bueno Gorka Jimenez , Baliani Alessandro , Klenke Burkhard , Brun Reto , Brock Janice M. , Gilbert Ian H. , Barrett Michael P. 
Published: April 2004

ABSTRACT

A series of nitroheterocyclic compounds were designed with linkages to melamine or benzamidine groups that are known substrates of the P2 aminopurine and other transporters in African trypanosomes of the brucei group. Several compounds showed in vitro trypanotoxicity with 50% inhibitory concentrations in the submicromolar range. Although most compounds interacted with the P2 transporter, as judged by their ability to inhibit adenosine transport via this carrier, uptake through this route was not necessary for activity since
TbAT1
-null mutant parasites, deficient in this transporter, retained sensitivity to these drugs. One compound, a melamine-linked nitrofuran, also showed pronounced activity against parasites in mice. Studies into the mode of action of this compound indicated that neither reductive, nor oxidative, stress were related to its trypanocidal activity ruling out a genotoxic effect in
T. brucei
, distinguishing it from some other, mammalian cell toxic, trypanocidal nitroheterocycles.
Activities of Benzimidazole
d
- and
l
-Ribonucleosides in Animal Models of Cytomegalovirus Infections
Authors: Kern Earl R. , Hartline Caroll B. , Rybak Rachel J. , Drach John C. , Townsend Leroy B. , Biron Karen K. , Bidanset Deborah J. 
Published: April 2004

ABSTRACT

Since human cytomegalovirus (HCMV) does not infect or replicate in nonhuman cells and tissues, there are few animal models currently available for evaluation of antiviral therapies for these infections. In the present studies, we utilized two different models in which severe combined immunodeficient (SCID) mice were implanted with human fetal tissue that was subsequently infected with HCMV. In one model, human fetal retinal tissue was implanted into the anterior chamber of the SCID mouse eye, and in the second, human fetal thymus and liver (thy/liv) tissues were implanted under the kidney capsule. After the implants were established, they were infected with 2,000 to 9,000 PFU of HCMV. To determine the efficacy of three benzimidazole nucleosides, 2-bromo-5,6-dichloro-(1-β-
d
-ribofuranosyl)benzimidazole (BDCRB), GW275175X (175X), and GW257406X (1263W94, maribavir [MBV]) treatment was initiated 24 h after infection of the implants and continued for 28 days. Treatment consisted of either placebo, 25 mg of ganciclovir (GCV)/kg of body weight administered intraperitoneally (i.p.) twice daily, 33 or 100 mg of BDCRB/kg administered i.p. twice daily, or 75 mg of either MBV or 175X/kg administered orally twice daily. GCV was effective in both models, inhibiting HCMV infection by 5- to 3,000-fold. In the retinal tissue model, MBV and BDCRB reduced HCMV replication about fourfold through 21 days postinfection compared with results for the vehicle control. In the thy/liv tissue model, all three benzimidazole nucleosides were effective in inhibiting HCMV replication by approximately 30- to 3,000-fold in comparison to the vehicle control. These data indicate that the benzimidazole nucleosides were efficacious in these animal models and suggest that this class of compounds should be active against the various HCMV infections that occur in the immunocompromised host.
Outcomes of Patients with Melioidosis Treated with Meropenem
Authors: Cheng Allen C. , Fisher Dale A. , Anstey Nicholas M. , Stephens Dianne P. , Jacups Susan P. , Currie Bart J. 
Published: April 2004

ABSTRACT

Melioidosis, an infection due to
Burkholderia pseudomallei
, is endemic in southeast Asia and northern Australia. We reviewed our experience with meropenem in the treatment of severe melioidosis in 63 patients over a 6-year period. Outcomes were similar to those of ceftazidime-treated patients (
n
= 153) despite a deliberate selection bias to more-unwell patients receiving meropenem. The mortality among meropenem-treated patients was 19%. One patient had a possible drug fever associated with the use of meropenem. We conclude that meropenem (1 g or 25 mg/kg every 8 h intravenously for ≥14 days) is an alternative to ceftazidime and imipenem in the treatment of melioidosis. The use of meropenem may be associated with improved outcomes in patients with severe sepsis associated with melioidosis.
Clinical Strains of
Pseudomonas aeruginosa
Overproducing MexAB-OprM and MexXY Efflux Pumps Simultaneously
Authors: Llanes Catherine , Hocquet Didier , Vogne Christelle , Benali-Baitich Dounia , Neuwirth Catherine , Plésiat Patrick 
Published: April 2004

ABSTRACT

Simultaneous overexpression of the MexAB-OprM and MexXY efflux systems was demonstrated by real-time reverse transcription-PCR and immunoblotting experiments for 12 multiresistant clinical isolates of
Pseudomonas aeruginosa
. DNA sequencing analysis showed that nine of these strains (named
agrZ
mutants) harbored mutations in
mexZ
, the product of which downregulates the expression of the
mexXY
operon. In addition, 8 of the 12 strains exhibited mutations in genes known to control transcription of the
mexAB-oprM
operon. Four of them were
nalB
mutants with alterations in the repressor gene
mexR
, three of them appeared to be
nalC
mutants deficient in gene
PA3721
and overexpressing gene
PA3720
, and one strain was a
nalB nalC
double mutant. For MexAB-OprM as well as for MexXY, no clear correlation could be established between (i) the types of mutations, (ii) the expression level of
mexA
or
mexX
, and (iii) resistance to effluxed antibiotics. Finally, three isolates, named
agrW
mutants, overproduced MexXY and had an intact
mexZ
gene, and four strains overproduced MexAB-OprM and had intact
mexR
and
PA3721
genes (
nalD
mutants). These data show that clinical isolates are able to broaden their drug resistance profiles by coexpressing two Mex efflux pumps and suggest the existence of additional regulators for MexAB-OprM and MexXY.
Novel, Rapid, and Inexpensive Cell-Based Quantification of Antimalarial Drug Efficacy
Authors: Bennett Tyler N. , Paguio Michelle , Gligorijevic Bojana , Seudieu Clement , Kosar Andrew D. , Davidson Eugene , Roepe Paul D. 
Published: April 2004

ABSTRACT

We report on the development of a new SYBR Green I-based plate assay for analyzing the activities of antimalarial drugs against intraerythrocytic
Plasmodium falciparum
. This assay is considerably faster, less labor-intensive, and less expensive than conventional radiotracer (e.g., [
3
H]hypoxanthine and [
3
H]ethanolamine)-based assays or
P. falciparum
lactate dehydrogenase activity-based assays. The assay significantly improves the pace at which antimalarial drug discovery efforts may proceed.
Novel Non-
mecA
-Containing Staphylococcal Chromosomal Cassette Composite Island Containing
pbp4
and
tagF
Genes in a Commensal Staphylococcal Species: a Possible Reservoir for Antibiotic Resistance Islands in
Staphylococcus aureus
Authors: Mongkolrattanothai Kanokporn , Boyle Susan , Murphy Trudy V. , Daum Robert S. 
Published: April 2004

ABSTRACT

Among methicillin-resistant
Staphylococcus aureus
isolates, a staphylococcal chromosomal cassette containing the
mecA
gene (SCC
mec
) is integrated into the chromosome at a unique site. SCC
mec
also contains unique
ccrAB
recombinase genes mediating its integration and excision from the genome and is flanked by characteristic left and right direct- and inverted-repeat sequences. A few non-
mecA
-containing SCC elements that have the other molecular features described above have recently been described. The origin of these cassettes is not clear. We have identified two new members of the SCC family integrated within
orfX
in
Staphylococcus epidermidis
strain ATCC 12228, neither of which carries
mecA
. One is a 57-kb element flanked by a unique 28-bp SCC direct repeat. It was called the SCC composite island (SCC-CI) because it carries a 19-kb SCC element (SCC
pbp4
) nested within it. SCC
pbp4
contains
pbp4
and
tagF
genes, as well as one pair of
ccrAB
genes (allotype 2) flanked by classical SCC-specific terminal repeats. External to SCC
pbp4
, SCC-CI contains a second pair of
ccrAB
genes (allotype 4), three IS
431
elements, and genes mediating resistance to heavy metals. Genes mediating restriction-modification that may facilitate horizontal transfer are also present within SCC-CI, both within and outside SCC
pbp4.
Several novel arrangements of the SCC direct and inverted repeats were identified. Several long stretches of homology with other SCCs were found within and outside SCC
pbp4
. In view of the fact that SCC-CI was found in a commensal species, it may represent a reservoir for sequences involved in genetic shuffling between staphylococci and may contribute to the diversity found in SCC elements.
Inhibitory Activity of Alkoxyalkyl and Alkyl Esters of Cidofovir and Cyclic Cidofovir against Orthopoxvirus Replication In Vitro
Authors: Keith Kathy A. , Wan William B. , Ciesla Stephanie L. , Beadle James R. , Hostetler Karl Y. , Kern Earl R. 
Published: April 2004

ABSTRACT
A new series of ether lipid esters of cidofovir (CDV) were evaluated against vaccinia and cowpox viruses. Activity was dependent on number of atoms in the alkyl or alkoxyalkyl chain, the linker moiety, and the presence of a double bond in the alkoxyalkyl chains linked to the phosphonate moiety of CDV.
Activities of Telithromycin against 13,874
Streptococcus pneumoniae
Isolates Collected between 1999 and 2003
Authors: Farrell David J. , Felmingham David 
Published: April 2004

ABSTRACT

Telithromycin MICs for 13,874
Streptococcus pneumoniae
isolates collected in the first 3 years of the global PROTEKT study (1999 to 2003) were studied. There was no change in the distribution of telithromycin MICs over this period, even in countries where telithromycin is in use. The telithromycin MICs for 10 isolates (0.07%) were ≥4 μg/ml, and these 10 isolates contained
erm
(B); there was no evidence of reproducible clonal spread between centers.