bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discovery of FabH/FabF Inhibitors from Natural Products
Authors: Young Katherine , Jayasuriya Hiranthi , Ondeyka John G. , Herath Kithsiri , Zhang Chaowei , Kodali Srinivas , Galgoci Andrew , Painter Ronald , Brown-Driver Vickie , Yamamoto Robert , Silver Lynn L. , Zheng Yingcong , Ventura Judith I. , Sigmund Janet , Ha Sookhee , Basilio Angela , Vicente Francisca , Tormo José Rubén , Pelaez Fernando , Youngman Phil , Cully Doris , Barrett John F. , Schmatz Dennis , Singh Sheo B. , Wang Jun 
Published: January 2006

ABSTRACT

Condensing enzymes are essential in type II fatty acid synthesis and are promising targets for antibacterial drug discovery. Recently, a new approach using a xylose-inducible plasmid to express antisense RNA in
Staphylococcus aureus
has been described; however, the actual mechanism was not delineated. In this paper, the mechanism of decreased target protein production by expression of antisense RNA was investigated using Northern blotting. This revealed that the antisense RNA acts posttranscriptionally by targeting mRNA, leading to 5′ mRNA degradation. Using this technology, a two-plate assay was developed in order to identify FabF/FabH target-specific cell-permeable inhibitors by screening of natural product extracts. Over 250,000 natural product fermentation broths were screened and then confirmed in biochemical assays, yielding a hit rate of 0.1%. All known natural product FabH and FabF inhibitors, including cerulenin, thiolactomycin, thiotetromycin, and Tü3010, were discovered using this whole-cell mechanism-based screening approach. Phomallenic acids, which are new inhibitors of FabF, were also discovered. These new inhibitors exhibited target selectivity in the gel elongation assay and in the whole-cell-based two-plate assay. Phomallenic acid C showed good antibacterial activity, about 20-fold better than that of thiolactomycin and cerulenin, against
S. aureus
. It exhibited a spectrum of antibacterial activity against clinically important pathogens including methicillin-resistant
Staphylococcus aureus
,
Bacillus subtilis
, and
Haemophilus influenzae
.
Inhibition of the Autolytic System by Vancomycin Causes Mimicry of Vancomycin-Intermediate
Staphylococcus aureus
-Type Resistance, Cell Concentration Dependence of the MIC, and Antibiotic Tolerance in Vancomycin-Susceptible
S. aureus
Authors: Sieradzki Krzysztof , Tomasz Alexander 
Published: January 2006

ABSTRACT

Treatment of the fully vancomycin-susceptible
Staphylococcus aureus
strain COL with subinhibitory concentrations of vancomycin allowed its continued growth but generated a phenotype reminiscent of some
S. aureus
isolates with vancomycin-intermediate
S. aureus
(VISA)-type resistance: the bacteria grew in multicellular clusters; electron microscopy showed inhibition of cell separation and accumulation of amorphous cell wall-like material at the bacterial surface. Titration of free vancomycin showed a gradual disappearance of the drug from the medium, which—eventually—coincided with an increase in the growth rate, burst in viable titer, and dispersal of cellular clusters. Addition of inhibitory concentrations of vancomycin to the same strain at a higher cell concentration caused a very different—antibiotic-tolerant—response: an immediate halt in growth, followed by a prolonged lag, during which there was neither a loss of viable titer or optical density nor a change in cell morphology but a gradual removal of vancomycin from the medium to the cell wall of the bacterium, from which the antibiotic could be recovered in a biologically active form. Eventually, the drug-treated culture resumed normal growth. The transient appearance of both the VISA phenotype and vancomycin tolerance could be traced to the inhibition of the autolytic system of the bacterium by vancomycin molecules attached to the cell wall, blocking the access of a staphylococcal murein hydrolase(s) to its cell wall substrate.
Horizontal Transfer of
bla
CMY
-Bearing Plasmids among Clinical
Escherichia coli
and
Klebsiella pneumoniae
Isolates and Emergence of Cefepime-Hydrolyzing CMY-19
Authors: Wachino Jun-ichi , Kurokawa Hiroshi , Suzuki Satowa , Yamane Kunikazu , Shibata Naohiro , Kimura Kouji , Ike Yasuyoshi , Arakawa Yoshichika 
Published: January 2006

ABSTRACT

Nine
Escherichia coli
and 5
Klebsiella pneumoniae
clinical isolates resistant to various cephalosporins and cephamycins were identified in a Japanese general hospital between 1995 and 1997. All nine
E. coli
isolates and one
K. pneumoniae
isolate carried
bla
CMY-9
, while the other four
K. pneumoniae
isolates harbored a variant of
bla
CMY-9
, namely,
bla
CMY-19
. The pulsed-field gel electrophoresis patterns of the nine CMY-9-producing
E. coli
isolates were almost identical, suggesting their clonal relatedness, while those of the five
K. pneumoniae
isolates were divergent. Plasmid profiles, Southern hybridization, and conjugation assays revealed that the genes for the CMY-9 and the CMY-19 β-lactamases were located on very similar conjugative plasmids in
E. coli
and
K. pneumoniae
. The genetic environment of
bla
CMY-19
was identical to that of
bla
CMY-9
. A single amino acid substitution, I292S, adjacent to the H-10 helix region was observed between CMY-9 and CMY-19. This substitution was suggested to be responsible for the expansion of the hydrolyzing activity against several broad-spectrum cephalosporins, and this finding was consistent with the kinetic parameters determined with purified enzymes. These findings suggest that the
bla
CMY-19
genes found in the four
K. pneumoniae
isolates might have originated from
bla
CMY-9
gene following a point mutation and dispersed among genetically different
K. pneumoniae
isolates via a large transferable plasmid.
Influence of Apigenin on
gtf
Gene Expression in
Streptococcus mutans
UA159
Authors: Koo Hyun , Seils Jennifer , Abranches Jacqueline , Burne Robert A. , Bowen William H. , Quivey Robert G. 
Published: January 2006

ABSTRACT

Apigenin, a potent inhibitor of glucosyltransferase activity, affects the accumulation of
Streptococcus mutans
biofilms in vitro by reducing the formation of insoluble glucans and enhancing the soluble glucan content of the polysaccharide matrix. In the present study, we investigated the influence of apigenin on
gtfB
,
gtfC
, and
gtfD
expression in
S. mutans
UA159. Apigenin (0.1 mM) significantly decreased the expression of
gtfB
and
gtfC
mRNA (
P
< 0.05); in contrast, it increased the expression of
gtfD
in
S. mutans
growing in the planktonic state. The protein levels of GTF B, GTF C, and GTF D in culture supernatants were also affected; less GTF B and C were detected, whereas the level of GTF D was significantly elevated (
P
< 0.05). A similar profile of
gtf
expression was obtained with biofilms, although an elevated concentration (1 mM) of apigenin was required to elicit the effects. The influence of apigenin on
gtf
gene expression was independent of any effect on GTF activity, did not involve inhibition of growth or effects on pH, and was not affected by addition of sucrose. The data show that apigenin modulates the genetic expression of virulence factors in
S. mutans.
In Vitro Antiretroviral Activity and In Vitro Toxicity Profile of SPD754, a New Deoxycytidine Nucleoside Reverse Transcriptase Inhibitor for Treatment of Human Immunodeficiency Virus Infection
Authors: Gu Z. , Allard B. , de Muys J. M. , Lippens J. , Rando R. F. , Nguyen-Ba N. , Ren C. , McKenna P. , Taylor D. L. , Bethell R. C. 
Published: January 2006

ABSTRACTSPD754 (AVX754) is a deoxycytidine analogue nucleotide reverse transcriptase inhibitor (NRTI) in clinical development. These studies characterized the in vitro activity of SPD754 against NRTI-resistant human immunodeficiency virus type 1 (HIV-1) and non-clade B HIV-1 isolates, its activity in combination with other antiretrovirals, and its potential myelotoxicity and mitochondrial toxicity. SPD754 was tested against 50 clinical HIV-1 isolates (5 wild-type isolates and 45 NRTI-resistant isolates) in MT-4 cells using the Antivirogram assay. SPD754 susceptibility was reduced 1.2- to 2.2-fold against isolates resistant to zidovudine (M41L, T215Y/F, plus a median of three additional nucleoside analogue mutations [NAMs]) and/or lamivudine (M184V) and was reduced 1.3- to 2.8-fold against isolates resistant to abacavir (L74V, Y115F, and M184V plus one other NAM) or stavudine (V75T/M, M41L, T215F/Y, and four other NAMs). Insertions at amino acid position 69 and Q151M mutations (with or without M184V) reduced SPD754 susceptibility 5.2-fold and 14- to 16-fold, respectively (these changes gave values comparable to or less than the corresponding values for zidovudine, lamivudine, abacavir, and didanosine). SPD754 showed similar activity against isolates of group M HIV-1 clades, including A/G, B, C, D, A(E), D/F, F, and H. SPD754 showed additive effects in combination with other NRTIs, tenofovir, nevirapine, or saquinavir. SPD754 had no significant effects on cell viability or mitochondrial DNA in HepG2 or MT-4 cells during 28-day exposure at concentrations up to 200 μM. SPD754 showed a low potential for myelotoxicity against human bone marrow. In vitro, SPD754 retained activity against most NRTI-resistant HIV-1 clinical isolates and showed a low propensity to cause myelotoxicity and mitochondrial toxicity.
Safety and Pharmacokinetics of Intravenous Anidulafungin in Children with Neutropenia at High Risk for Invasive Fungal Infections
Authors: Benjamin Daniel K. , Driscoll Timothy , Seibel Nita L. , Gonzalez Corina E. , Roden Maureen M. , Kilaru Rahki , Clark Kay , Dowell James A. , Schranz Jennifer , Walsh Thomas J. 
Published: January 2006

ABSTRACT

Anidulafungin is an echinocandin with activity against
Candida
species and
Aspergillus
species. Adult dosages under study are 50 mg/day for esophageal candidiasis and 100 mg/day for invasive candidiasis and aspergillosis. Little is known, however, about the safety and pharmacokinetics of anidulafungin in children. A multicenter, ascending-dosage study of neutropenic pediatric patients was therefore conducted. Patients were divided into two age cohorts (2 to 11 years and 12 to 17 years) and were enrolled into sequential groups to receive 0.75 or 1.5 mg/kg of body weight/day. Blood samples were obtained following the first and fifth doses. Anidulafungin was assayed in plasma, and pharmacokinetic parameters were determined. Safety was assessed using National Cancer Institute (NCI) common toxicity criteria. Pharmacokinetic parameters were determined for 12 patients at each dosage (0.75 mg/kg/day or 1.5 mg/kg/day). Concentrations and drug exposures were similar for patients between age cohorts, and weight-adjusted clearance was consistent across age. No drug-related serious adverse events were observed. One patient had fever (NCI toxicity grade of 3), and one patient had facial erythema, which resolved with slowing the infusion rate. Anidulafungin in pediatric patients was well tolerated and can be dosed based on body weight. Pediatric patients receiving 0.75 mg/kg/day or 1.5 mg/kg/day have anidulafungin concentration profiles similar to those of adult patients receiving 50 or 100 mg/day, respectively.
Potencies of Human Immunodeficiency Virus Protease Inhibitors In Vitro againstPlasmodium falciparumand In Vivo against Murine Malaria
Authors: Andrews Katherine T. , Fairlie David P. , Madala Praveen K. , Ray John , Wyatt David M. , Hilton Petrina M. , Melville Lewis A. , Beattie Lynette , Gardiner Donald L. , Reid Robert C. , Stoermer Martin J. , Skinner-Adams Tina , Berry Colin , McCarthy James S. 
Published: January 2006

ABSTRACTParasite resistance to antimalarial drugs is a serious threat to human health, and novel agents that act on enzymes essential for parasite metabolism, such as proteases, are attractive targets for drug development. Recent studies have shown that clinically utilized human immunodeficiency virus (HIV) protease inhibitors can inhibit the in vitro growth ofPlasmodium falciparumat or below concentrations found in human plasma after oral drug administration. The most potent in vitro antimalarial effects have been obtained for parasites treated with saquinavir, ritonavir, or lopinavir, findings confirmed in this study for a genetically distinctP. falciparumline (3D7). To investigate the potential in vivo activity of antiretroviral protease inhibitors (ARPIs) against malaria, we examined the effect of ARPI combinations in a murine model of malaria. In mice infected withPlasmodium chabaudiAS and treated orally with ritonavir-saquinavir or ritonavir-lopinavir, a delay in patency and a significant attenuation of parasitemia were observed. Using modeling and ligand docking studies we examined putative ligand binding sites of ARPIs in aspartyl proteases ofP. falciparum(plasmepsins II and IV) andP. chabaudi(plasmepsin) and found that these in silico analyses support the antimalarial activity hypothesized to be mediated through inhibition of these enzymes. In addition, in vitro enzyme assays demonstrated thatP. falciparumplasmepsins II and IV are both inhibited by the ARPIs saquinavir, ritonavir, and lopinavir. The combined results suggest that ARPIs have useful antimalarial activity that may be especially relevant in geographical regions where HIV andP. falciparuminfections are both endemic.
Quinolones Induce Partial or Total Loss of Pathogenicity Islands in Uropathogenic
Escherichia coli
by SOS-Dependent or -Independent Pathways, Respectively
Authors: Soto S. M. , Jimenez de Anta M. T. , Vila J. 
Published: January 2006

ABSTRACT

Escherichia coli
is the most common microorganism causing urinary tract infections. Quinolone-resistant
E. coli
strains have fewer virulence factors than quinolone-susceptible strains. Several urovirulence genes are located in pathogenicity islands (PAIs). We investigated the capacity of quinolones to induce loss of virulence factors such as hemolysin, cytotoxic necrotizing factor 1, P fimbriae, and autotransporter Sat included in PAIs in three uropathogenic
E. coli
strains. In a multistep selection, all strains lost hemolytic capacity at between 1 and 4 passages when they were incubated with subinhibitory concentrations of ciprofloxacin, showing a partial or total loss of the PAI containing the
hly
(hemolysin) and
cnf-1
(cytotoxic necrotizing factor 1) genes. RecA
−
mutants were obtained from the two
E. coli
strains with partial or total loss of the PAI. The inactivation of the RecA protein affected only the partial loss of the PAI induced by quinolones. No spontaneous loss of PAIs was observed on incubation in the absence of quinolones in either the wild-type or mutant
E. coli
strains. Quinolones induce partial or total loss of PAIs in vitro in uropathogenic
E. coli
by SOS-dependent or -independent pathways, respectively.
Involvement of the Putative ATP-Dependent Efflux Proteins PatA and PatB in Fluoroquinolone Resistance of a Multidrug-Resistant Mutant of
Streptococcus pneumoniae
Authors: Marrer Estelle , Schad Karen , Satoh Andreas T. , Page Malcolm G. P. , Johnson Maggie M. , Piddock Laura J. V. 
Published: January 2006

ABSTRACT

The multidrug-resistant mutant
Streptococcus pneumoniae
M22 constitutively overexpresses two genes (
patA
and
patB
) that encode proteins homologous to known efflux proteins belonging to the ABC transporter family. It is shown here that PatA and PatB were strongly induced by quinolone antibiotics and distamycin in fluoroquinolone-sensitive strains. PatA was very important for growth of
S. pneumoniae
, and it could not be disrupted in strain M22. PatB appeared to control metabolic activity, particularly in amino acid biosynthesis, and it may have a pivotal role in coordination of the response to quinolone antibiotics. The induction of PatA and PatB by antibiotics showed a pattern similar to that exhibited by SP1861, a homologue of ABC-type transporters of choline and other osmoprotectants. A second group of quinolone-induced transporter genes comprising SP1587 and SP0287, which are homologues of, respectively, oxalate/formate antiporters and xanthine or uracil permeases belonging to the major facilitator family, showed a different pattern of induction by other antibiotics. There was no evidence for the involvement of PmrA, the putative proton-dependent multidrug transporter that has been implicated in norfloxacin resistance, in the response to quinolone antibiotics in either the resistant mutant or the fluoroquinolone-sensitive strains.
Rational Design of Anticytoadherence Inhibitors forPlasmodium falciparumBased on the Crystal Structure of Human Intercellular Adhesion Molecule 1
Authors: Dormeyer Matthias , Adams Yvonne , Kramer Bernd , Chakravorty Srabasti , Tse Man Tsuey , Pegoraro Stefano , Whittaker Lisa , Lanzer Michael , Craig Alister 
Published: January 2006

ABSTRACTAdhesion ofPlasmodium falciparum-infected erythrocytes (IE) to host endothelium has been associated with pathology in malaria. Although the interaction with endothelial cells can be complex due to the relatively large number of host receptors available for binding, specific proteins have been identified that are more commonly used than others. For example, binding to intercellular adhesion molecule 1 (ICAM 1) is found frequently in parasites from pediatric cases of malaria. The binding site forP. falciparum-infected erythrocytes on ICAM 1 has been mapped in some detail and is distinct from the site for lymphocyte function-associated antigen 1 (LFA-1). Part of the ICAM 1 binding site forP. falciparum-infected erythrocytes (the DE loop) was used to screen a library of compounds based on its structure (derived from the crystal structure of human ICAM 1). This resulted in the identification of 36 structural mimeotopes as potential competitive inhibitors of binding. One of these compounds, (+)-epigalloyl-catechin-gallate [(+)-EGCG], was found to inhibit IE adhesion to ICAM 1 in a dose-dependent manner with two variant ICAM 1-binding parasite lines, providing the first example of a potential mimeotope-based anticytoadherence inhibitor forPlasmodium falciparum.
Doxycycline Attenuated Pulmonary Fibrosis Induced by Bleomycin in Mice
Authors: Fujita Masaki , Ye Qing , Ouchi Hiroshi , Harada Eiji , Inoshima Ichiro , Kuwano Kazuyoshi , Nakanishi Yoichi 
Published: January 2006

ABSTRACTThe administration of doxycycline prior to bleomycin in mice attenuated pulmonary fibrosis. Bronchoalveolar neutrophil influx and gelatinase activity, but not caseinolytic activity, were attenuated by doxycycline. Established fibrosis was not affected by doxycycline. Thus, doxycycline might be useful for slowing down pulmonary fibrosis by biological activity other than antibacterial activity.
Practical Preclinical Model for Assessing the Potential for Unconjugated Hyperbilirubinemia Produced by Human Immunodeficiency Virus Protease Inhibitors
Authors: Kempf Dale J. , Waring Jeffrey F. , Morfitt David C. , Werner Paige , Ebert Brian , Mitten Michael , Nguyen Bach , Randolph John T. , DeGoey David A. , Klein Larry L. , Marsh Kennan 
Published: January 2006

ABSTRACT
A practical preclinical model for the hyperbilirubinemia produced by human immunodeficiency virus protease inhibitors has been developed. Indinavir and atazanavir produced significant hyperbilirubinemia, whereas amprenavir, the negative control, was indistinguishable from the ritonavir booster dose. This model was used to disqualify an exploratory protease inhibitor from development.
Single- and Multistep Resistance Selection Studies on the Activity of Retapamulin Compared to Other Agents against
Staphylococcus aureus
and
Streptococcus pyogenes
Authors: Kosowska-Shick Klaudia , Clark Catherine , Credito Kim , McGhee Pamela , Dewasse Bonifacio , Bogdanovich Tatiana , Appelbaum Peter C. 
Published: January 2006

ABSTRACT

Retapamulin had the lowest rate of spontaneous mutations by single-step passaging and the lowest parent and selected mutant MICs by multistep passaging among all drugs tested for all
Staphylococcus aureus
strains and three
Streptococcus pyogenes
strains which yielded resistant clones. Retapamulin has a low potential for resistance selection in
S. pyogenes
, with a slow and gradual propensity for resistance development in
S. aureus
.
Tissue Penetration of Telavancin after Intravenous Administration in Healthy Subjects
Authors: Sun Heather K. , Duchin Kenneth , Nightingale Charles H. , Shaw Jeng-Pyng , Seroogy Julie , Nicolau David P. 
Published: January 2006

ABSTRACT
The pharmacokinetic disposition of telavancin administered 7.5 mg/kg of body weight every 24 h was determined in plasma and skin blister fluid. The mean penetration of telavancin into blister fluid was 40%. This study reveals that adequate concentrations are achieved in both plasma and blister fluid for pathogens frequently implicated in skin and soft tissue infections.
PCR Classification of CTX-M-Type β-Lactamase Genes Identified in Clinically Isolated Gram-Negative Bacilli in Japan
Authors: Shibata Naohiro , Kurokawa Hiroshi , Doi Yohei , Yagi Tetsuya , Yamane Kunikazu , Wachino Jun-ichi , Suzuki Satowa , Kimura Kouji , Ishikawa Satoshi , Kato Haru , Ozawa Yoshiyuki , Shibayama Keigo , Kai Kumiko , Konda Toshifumi , Arakawa Yoshichika 
Published: January 2006

ABSTRACT

Of 1,456 strains isolated from 2001 to 2003 demonstrating resistance to either oxyimino-cephalosporin, 317 strains, isolated in 57 of 132 clinical facilities, were found to harbor
bla
CTX-M
genes by PCR. Fifty-seven, 161, and 99 strains harbored
bla
CTX-M
genes belonging to the
bla
CTX-M-1
,
bla
CTX-M-2
, and
bla
CTX-M-9
clusters, respectively.
A randomised control study of a fully automated internet based smoking cessation programme
Authors: Swartz L H G , Noell J W , Schroeder S W , Ary D V 
Published: January 2006

Objective:The objective of this project was to test the short term (90 days) efficacy of an automated behavioural intervention for smoking cessation, the “1-2-3 Smokefree” programme, delivered via an internet website.Design:Randomised control trial. Subjects surveyed at baseline, immediately post-intervention, and 90 days later.Settings:The study and the intervention occurred entirely via the internet site. Subjects were recruited primarily via worksites, which referred potential subjects to the website.Subjects:The 351 qualifying subjects were notified of the study via their worksite and required to have internet access. Additionally, subjects were required to be over 18 years of age, smoke cigarettes, and be interested in quitting smoking in the next 30 days. Eligible subjects were randomly assigned individually to treatment or control condition by computer algorithm.Intervention:The intervention consisted of a video based internet site that presented current strategies for smoking cessation and motivational materials tailored to the user’s race/ethnicity, sex, and age. Control subjects received nothing for 90 days and were then allowed access to the programme.Main outcome measures:The primary outcome measure was abstinence from smoking at 90 day follow up.Results:At follow up, the cessation rate at 90 days was 24.1% (n  =  21) for the treatment group and 8.2% (n  =  9) for the control group (p  =  0.002). Using an intent-to-treat model, 12.3% (n  =  21) of the treatment group were abstinent, compared to 5.0% (n  =  9) in the control group (p  =  0.015).Conclusions:These evaluation results suggest that a smoking cessation programme, with at least short term efficacy, can be successfully delivered via the internet.