bluuebunny/crossref_metadata_2025_split huggingface dataset:
N-Substituted Pyrrole Derivatives as Novel Human Immunodeficiency Virus Type 1 Entry Inhibitors That Interfere with the gp41 Six-Helix Bundle Formation and Block Virus Fusion
Authors: Jiang Shibo , Lu Hong , Liu Shuwen , Zhao Qian , He Yuxian , Debnath Asim K. 
Published: October 2004

ABSTRACT

A recently approved peptidic human immunodeficiency virus type 1 (HIV-1) fusion inhibitor, T-20 (Fuzeon; Trimeris Inc.), has shown significant promise in clinical application for treating HIV-1-infected individuals who have failed to respond to the currently available antiretroviral drugs. However, T-20 must be injected twice daily and is too expensive. Therefore, it is essential to develop orally available small molecule HIV-1 fusion inhibitors. By screening a chemical library consisting of “drug-like” compounds, we identified two N-substituted pyrroles, designated NB-2 and NB-64, that inhibited HIV-1 replication at a low micromolar range. The absence of the COOH group in NB-2 and NB-64 resulted in a loss of anti-HIV-1 activity, suggesting that this acid group plays an important role in mediating the antiviral activity. NB-2 and NB-64 inhibited HIV-1 fusion and entry by interfering with the gp41 six-helix bundle formation and disrupting the α-helical conformation. They blocked a
d-
peptide binding to the hydrophobic pocket on surface of the gp41 internal trimeric coiled-coil domain. Computer-aided molecular docking analysis has shown that they fit inside the hydrophobic pocket and that their COOH group interacts with a positively charged residue (K574) around the pocket to form a salt bridge. These results suggest that NB-2 and NB-64 may bind to the gp41 hydrophobic pocket through hydrophobic and ionic interactions and block the formation of the fusion-active gp41 core, thereby inhibiting HIV-1-mediated membrane fusion and virus entry. Therefore, NB-2 and NB-64 can be used as lead compounds toward designing and developing more potent small molecule HIV-1 fusion inhibitors targeting gp41.
Usnic Acid, a Natural Antimicrobial Agent Able To Inhibit Bacterial Biofilm Formation on Polymer Surfaces
Authors: Francolini I. , Norris P. , Piozzi A. , Donelli G. , Stoodley P. 
Published: October 2004

ABSTRACT

In modern medicine, artificial devices are used for repair or replacement of damaged parts of the body, delivery of drugs, and monitoring the status of critically ill patients. However, artificial surfaces are often susceptible to colonization by bacteria and fungi. Once microorganisms have adhered to the surface, they can form biofilms, resulting in highly resistant local or systemic infections. At this time, the evidence suggests that (+)-usnic acid, a secondary lichen metabolite, possesses antimicrobial activity against a number of planktonic gram-positive bacteria, including
Staphylococcus aureus
,
Enterococcus faecalis
, and
Enterococcus faecium
. Since lichens are surface-attached communities that produce antibiotics, including usnic acid, to protect themselves from colonization by other bacteria, we hypothesized that the mode of action of usnic acid may be utilized in the control of medical biofilms. We loaded (+)-usnic acid into modified polyurethane and quantitatively assessed the capacity of (+)-usnic acid to control biofilm formation by either
S. aureus
or
Pseudomonas aeruginosa
under laminar flow conditions by using image analysis. (+)-Usnic acid-loaded polymers did not inhibit the initial attachment of
S. aureus
cells, but killing the attached cells resulted in the inhibition of biofilm. Interestingly, although
P. aeruginosa
biofilms did form on the surface of (+)-usnic acid-loaded polymer, the morphology of the biofilm was altered, possibly indicating that (+)-usnic acid interfered with signaling pathways.
Analysis of Mupirocin Resistance and Fitness in
Staphylococcus aureus
by Molecular Genetic and Structural Modeling Techniques
Authors: Hurdle Julian Gregston , O'Neill Alexander John , Ingham Eileen , Fishwick Colin , Chopra Ian 
Published: October 2004

ABSTRACT

Chromosomal resistance to mupirocin in clinical isolates of
Staphylococcus aureus
arises from V
588
F or V
631
F mutations in isoleucyl-tRNA synthetase (IRS). Whether these are the only IRS mutations that confer mupirocin resistance or simply those that survive in the clinic is unknown. Mupirocin-resistant mutants of
S. aureus
8325-4 were therefore generated to examine their
ileS
genotypes and the in vitro and in vivo fitness costs associated with them before and after compensatory evolution. Most spontaneous first-step mupirocin-resistant mutants carried V
588
F or V
631
F mutations in IRS, but a new mutation (G
593
V) was also identified. Second-step mutants carried combinations of previously identified IRS mutations (e.g., V
588
F/V
631
F and G
593
V/V
631
F), but additional combinations also occurred involving novel mutations (R
816
C, H
67
Q, and F
563
L). First-step mupirocin-resistant mutants were not associated with substantial fitness costs, a finding that is consistent with the occurrence of V
588
F or V
631
F mutations in the IRS of clinical strains. Second-step mutants were unfit, but fitness could be restored by subculture in the absence of mupirocin. In most cases, this was the result of compensatory mutations that also suppressed mupirocin resistance (e.g., A
196
V, E
190
K, and E
195
K), despite retention of the original mutations conferring resistance. Structural explanations for mupirocin resistance and loss of fitness were obtained by molecular modeling of mutated IRS enzymes, which provided data on mupirocin binding and interaction with the isoleucyl-AMP reactive intermediate.
In Vitro Combination of Amdoxovir and the Inosine Monophosphate Dehydrogenase Inhibitors Mycophenolic Acid and Ribavirin Demonstrates Potent Activity against Wild-Type and Drug-Resistant Variants of Human Immunodeficiency Virus Type 1
Authors: Borroto-Esoda Katyna , Myrick Florence , Feng Joy , Jeffrey Jerry , Furman Phillip 
Published: October 2004

ABSTRACT

Amdoxovir [(−)-β-
d
-2,6-diaminopurine dioxolane (DAPD)] is a nucleoside analogue reverse transcriptase inhibitor of human immunodeficiency virus type 1 (HIV-1) replication. DAPD is deaminated by adenosine deaminase to the guanosine analogue dioxolane guanosine (DXG), which is subsequently phosphorylated to the corresponding 5′ triphosphate (DXG-TP). DXG-TP competes with the natural substrate dGTP for binding to the enzyme-nucleic acid complex. Mycophenolic acid (MPA) and ribavirin (RBV), inhibitors of inosine monophosphate dehydrogenase (IMPDH), inhibit the de novo synthesis of guanine nucleotides, including dGTP. Reducing the intracellular levels of dGTP would be expected to augment the antiviral activity of analogues of deoxyguanosine. In this study we examined the effect of MPA and RBV on the anti-HIV activity of DAPD and DXG. When tested against wild-type virus, both MPA and RBV decreased the 50% effective concentration (EC
50
) for DXG by at least 10-fold. In contrast, both MPA and RBV increase the EC
50
value for zidovudine. MPA and RBV completely reversed the resistance to DXG observed with HIV isolates containing mutations which confer partial resistance to DAPD and DXG. Similarly, when tested against a mutant virus fully resistant to inhibition by DAPD (K65R/Q151M), MPA and RBV reduced the EC
50
for DAPD to within twofold of that for the wild type. The combination of MPA or RBV with DAPD or DXG did not result in increased cytotoxicity or reduced levels of mitochondrial DNA when tested at physiologically relevant concentrations. These studies suggest a potential role for the use of IMPDH inhibitors in combination therapy with amdoxovir in the treatment of HIV.
Platelet Microbicidal Protein 1: Structural Themes of a Multifunctional Antimicrobial Peptide
Authors: Yount Nannette Y. , Gank Kimberly D. , Xiong Yan Qiong , Bayer Arnold S. , Pender Thomas , Welch William H. , Yeaman Michael R. 
Published: October 2004

ABSTRACTMammalian platelets release platelet microbicidal proteins (PMPs) as components of their antimicrobial armamentarium. The present studies defined the structure of PMP-1 and examined its structure-activity relationships. Amino acid sequencing and mass spectroscopy demonstrated that distinct N-terminal polymorphism variants of PMP-1 isolated from nonstimulated or thrombin-stimulated platelets arise from a single PMP-1 propeptide. Sequence data (NH2-[S]D1DPKE5SEGDL10HCVCV15KTTSL20. . .) enabled cloning of PMP-1 from bone marrow and characterization of its full-length cDNA. PMP-1 is translated as a 106-amino-acid precursor and is processed to yield 73-residue (8,053 Da) and 72-residue (7,951-Da) variants. Searches with the BLAST program and sequence alignments demonstrated the homology of PMP-1 to members of the mammalian platelet factor 4 (PF-4) family of proteins. On the basis of phylogenetic relatedness, congruent sequence motifs, and predicted three-dimensional structures, PMP-1 shares the greatest homology with human PF-4 (hPF-4). By integration of its structural and antimicrobial properties, these results establish the identity of PMP-1 as a novel rabbit analogue of the microbicidal chemokine (kinocidin) hPF-4. These findings advance the hypothesis that stimuli in the setting of infection prompt platelets to release PF-4-class or related kinocidins, which have structures consistent with their likely multiple roles that bridge molecular and cellular mechanisms of antimicrobial host defense.
Anti-
Aspergillus fumigatus
Efficacy of Pentraxin 3 Alone and in Combination with Antifungals
Authors: Gaziano Roberta , Bozza Silvia , Bellocchio Silvia , Perruccio Katia , Montagnoli Claudia , Pitzurra Lucia , Salvatori Giovanni , De Santis Rita , Carminati Paolo , Mantovani Alberto , Romani Luigina 
Published: October 2004

ABSTRACT

The collectin pentraxin 3 (PTX3) is an essential component of host resistance to pulmonary aspergillosis. Here we examined the protective effects of administration of PTX3 alone or together with deoxycholate amphotericin B (Fungizone) or liposomal amphotericin B (AmBisome) against invasive aspergillosis in a murine model of allogeneic bone marrow transplantation. PTX3, alone or in combination with the polyenes, was given intranasally or parenterally either before, in concomitance with, or after the intranasal infection with
Aspergillus fumigatus
conidia. Mice were monitored for resistance to infection and parameters of innate and adaptive T-helper immunity. The results showed the following: (i) complete resistance to infection and reinfection was observed in mice treated with PTX3 alone; (ii) the protective effect of PTX3 was similar or superior to that observed with liposomal amphotericin B or deoxycholate amphotericin B, respectively; (iii) protection was associated with accelerated recovery of lung phagocytic cells and T-helper-1 lymphocytes and concomitant decrease of inflammatory pathology; and (iv) PTX3 potentiated the therapeutic efficacy of suboptimal doses of either antimycotic drug. Together, these data suggest the potential therapeutic use of PTX3 either alone or as an adjunctive therapy in
A. fumigatus
infections.
Dose-Dependent Resorption of Quinine after Intrarectal Administration to Children with Moderate
Plasmodium falciparum
Malaria
Authors: Pussard Eric , Straczek Celine , Kaboré Idrissa , Bicaba Auguste , Balima-Koussoube Tatiana , Bouree Patrice , Barennes Hubert 
Published: October 2004

ABSTRACT
The pharmacokinetics of increasing doses of an intrarectal Cinchona alkaloid combination containing 96.1% quinine, 2.5% quinidine, 0.68% cinchonine, and 0.67% cinchonidine (Quinimax) was compared to that of parenteral regimens in 60 children with moderate malaria. Quinine exhibited a nonlinear pharmacokinetics, suggesting a saturation of rectal resorption. When early rejections appeared, blood quinine concentrations decreased by 30 to 50% and were restored by an immediate half-dose administration of the drug. Rectal administration of doses of 16 or 20 mg/kg of body weight led to concentration-time profiles in blood similar to those of parenteral regimens and could be an early treatment of childhood malaria.
Activity of OPT-80, a Novel Macrocycle, Compared with Those of Eight Other Agents against Selected Anaerobic Species
Authors: Credito Kim L. , Appelbaum Peter C. 
Published: October 2004

ABSTRACT

Agar dilution MIC was used to compare activities of OPT-80, linezolid, vancomycin, teicoplanin, quinupristin/dalfopristin, amoxicillin/clavulanate, imipenem, clindamycin, and metronidazole against 350 gram-positive and -negative anaerobes. OPT-80 was active against gram-positive strains only, especially
Clostridium
spp. (85 strains tested, including 21 strains of
C. difficile
), with MICs ranging between ≤0.016 and 0.25 μg/ml.
Community-Onset Disease Caused by
Citrobacter freundii
Producing a Novel CTX-M β-Lactamase, CTX-M-30, in Canada
Authors: Abdalhamid Baha , Pitout Johann D. D. , Moland Ellen S. , Hanson Nancy D. 
Published: October 2004

ABSTRACT

Strains of
Citrobacter freundii
intermediate to cefotaxime but sensitive to ceftazidime were isolated from four different patients in Canada. Sequencing of PCR products by use of CTX-M-specific primers revealed a new combination of four amino acid substitutions. This new gene was designated
bla
CTX-M-30
and was encoded on a 3-kb plasmid. The pI of CTX-M-30 was 8.0.
Plasmid-Mediated Carbapenem-Hydrolyzing Enzyme KPC-2 in an
Enterobacter
sp
Authors: Hossain Ashfaque , Ferraro M. J. , Pino R. M. , Dew R. B. , Moland E. S. , Lockhart T. J. , Thomson K. S. , Goering R. V. , Hanson N. D. 
Published: October 2004

ABSTRACT

A strain of an
Enterobacter
sp. with reduced susceptibility to imipenem, which produced a plasmid-mediated class A carbapenem-hydrolyzing enzyme, KPC-2 β-lactamase, was isolated from a patient with sepsis at a Boston hospital. This is the first report of the production of a plasmid-encoded KPC-2 β-lactamase by an
Enterobacter
sp.
Altered Susceptibility of
Candida glabrata
Bloodstream Isolates to Triazoles at Clinically Relevant pH Values: Comparison of the NCCLS M27-A2, Sensititre YeastOne, and Etest Methods
Authors: Pai Manjunath P. , Jones Ariel L. 
Published: October 2004

ABSTRACT

We studied the MICs of triazoles against 15
Candida glabrata
clinical isolates by the NCCLS M27-A2, Sensititre YeastOne, and Etest methods by using media at pHs 6.0, 7.0, and 7.4. Thirteen isolates were less susceptible to triazoles at pH 6.0 and more susceptible to triazoles at pH 7.4 compared to pH 7.0.
Antibiotic Susceptibility in Neonatal Invasive Isolates of
Streptococcus agalactiae
in a 2-Year Nationwide Surveillance Study in Germany
Authors: Fluegge Kirsten , Supper Sven , Siedler Anette , Berner Reinhard 
Published: October 2004

ABSTRACT

The antimicrobial susceptibility of 296 invasive neonatal group B streptococcus isolates from a nationwide 2-year surveillance study in Germany was investigated. All isolates were susceptible to beta-lactams, linezolid, quinupristin-dalfopristin, and vancomycin. Erythromycin and clindamycin resistance was found in 10.1 and 5.7%, respectively. The
ermB
,
ermTR
, or
mefA
gene was detected in all but one of the erythromycin-resistant isolates.
Antimicrobial and Antileishmanial Activities of Hypocrellins A and B
Authors: Ma Guoyi , Khan Shabana I. , Jacob Melissa R. , Tekwani Babu L. , Li Zuqiang , Pasco David S. , Walker Larry A. , Khan Ikhlas A. 
Published: October 2004

ABSTRACT

Hypocrellins A and B were evaluated for in vitro antimicrobial and antileishmanial activities. Hypocrellin A exhibited promising activity against
Candida albicans
and moderate activity against
Staphylococcus aureus
, methicillin-resistant
S. aureus
,
Pseudomonas aeruginosa
, and
Mycobacterium intracellulare
. Hypocrellin B showed weak antimicrobial activities. Hypocrellin A exhibited potent antileishmanial activity, while hypocrellin B was only moderately active. These results of promising antifungal and antileishmanial activity of hypocrellin A may be useful for further structure-activity relationship and in vivo studies.
In Vitro Pharmacodynamic Characteristics of Amphotericin B, Caspofungin, Fluconazole, and Voriconazole against Bloodstream Isolates of Infrequent
Candida
Species from Patients with Hematologic Malignancies
Authors: Di Bonaventura Giovanni , Spedicato Ilaria , Picciani Carla , D'Antonio Domenico , Piccolomini Raffaele 
Published: October 2004

ABSTRACT

Time-kill and postantifungal effect (PAFE) of amphotericin B, caspofungin, fluconazole, and voriconazole were determined against clinical isolates of
Candida guilliermondii
,
Candida kefyr
, and
Candida lusitaniae
. Azoles displayed fungistatic activity and no measurable PAFE, regardless of the concentration tested. Amphotericin B and caspofungin demonstrated concentration-dependent fungicidal activity, although amphotericin B only produced a significant dose-dependent PAFE against all isolates tested.
Evaluation of a Colorimetric Antifungal Susceptibility Test by Using 2,3-Diphenyl-5-Thienyl-(2)-Tetrazolium Chloride
Authors: Shin Jeong Hwan , Choi Jae-Cheol , Lee Jeong Nyeo , Kim Hyung Hoi , Lee Eun Yup , Chang Chulhun Ludgerus 
Published: October 2004

ABSTRACT

A colorimetric antifungal susceptibility test was performed using 2,3-diphenyl-5-thienyl-(2)-tetrazolium chloride. Among 24 strains of
Candida
species, no trailing growth was found. In 22 and 20 strains, the MICs obtained in the colorimetric assay were within two dilutions of those obtained by the National Committee for Clinical Laboratory Standards method for ketoconazole and itraconazole, respectively.
Quinolone-Resistant
Haemophilus influenzae
: Determination of Mutant Selection Window for Ciprofloxacin, Garenoxacin, Levofloxacin, and Moxifloxacin
Authors: Li Xinying , Mariano Noriel , Rahal James J. , Urban Carl M. , Drlica Karl 
Published: October 2004

ABSTRACT

Stepwise selection of ciprofloxacin-resistant
Haemophilus influenzae
mutants produced first-, second-, third-, and fourth-step substitutions in GyrA (S84Y), ParC (S84R), GyrA (D88N), and ParC (E88K), respectively. Successive mutations raised the mutant selection window. The wild-type selection window for garenoxacin, levofloxacin, and moxifloxacin was also measured.
SHV-49, a Novel Inhibitor-Resistant β-Lactamase in a Clinical Isolate of
Klebsiella pneumoniae
Authors: Dubois Véronique , Poirel Laurent , Arpin Corinne , Coulange Laure , Bebear Cécile , Nordmann Patrice , Quentin Claudine 
Published: October 2004

ABSTRACT

A clinical strain of
Klebsiella pneumoniae
carried the
bla
SHV-49
gene, encoding a novel inhibitor-resistant β-lactamase of pI 7.6, derived from SHV-1 by the single substitution M69I. It also harbored a gene differing from
bla
SHV-11
by four silent mutations and coding for a penicillinase. Both genes were chromosome located and might represent either a species-specific gene or an acquired resistance gene.
In Vitro Susceptibilities of
Mycoplasma hyopneumoniae
Field Isolates
Authors: Vicca J. , Stakenborg T. , Maes D. , Butaye P. , Peeters J. , de Kruif A. , Haesebrouck F. 
Published: October 2004

ABSTRACT

The in vitro susceptibilities of 21
Mycoplasma hyopneumoniae
field isolates were determined using a broth microdilution technique. One isolate showed acquired resistance to lincomycin, tilmicosin, and tylosin, while five isolates were resistant to flumequine and enrofloxacin. Acquired resistance against these antimicrobials in
M. hyopneumoniae
field isolates was not reported previously.
Decreased Bioavailability of Rifampin and Other Antituberculosis Drugs in Patients with Advanced Human Immunodeficiency Virus Disease
Authors: Gurumurthy Prema , Ramachandran Geetha , Hemanth Kumar A. K. , Rajasekaran S. , Padmapriyadarsini C. , Swaminathan Soumya , Bhagavathy S. , Venkatesan P. , Sekar L. , Mahilmaran A. , Ravichandran N. , Paramesh P. 
Published: October 2004

ABSTRACT
We evaluated the effects of human immunodeficiency virus (HIV) disease on pharmacokinetics of antituberculosis medications by measuring concentrations of isoniazid and rifampin in blood and of pyrazinamide and ethambutol in urine. Peak concentration and exposure were reduced for rifampin, and rapid acetylators of isoniazid had lower drug levels. HIV and HIV-tuberculosis patients who have diarrhea and cryptosporidial infection exhibit decreased bioavailability of antituberculosis drugs.
Activity of Tigecycline (GAR-936) against
Acinetobacter baumannii
Strains, Including Those Resistant to Imipenem
Authors: Pachón-Ibáñez María Eugenia , Jiménez-Mejías Manuel Enrique , Pichardo Cristina , Llanos Ana Cristina , Pachón Jerónimo 
Published: October 2004

ABSTRACT

We determined the in vitro activities of tigecycline and imipenem against 49 isolates of
Acinetobacter baumannii
, including those resistant to imipenem. The MIC at which 50% of the isolates were inhibited (MIC
50
) and the MIC
90
for tigecycline and imipenem were 2 and 2 mg/liter and 32 and 128 mg/liter, respectively, with 92 and 20%, respectively, of the strains being susceptible. Tigecycline did not show bactericidal activity in the time-kill studies (
n
= 9 strains). Imipenem showed bactericidal activity against seven out of nine strains. These in vitro results show that tigecycline has good in vitro bacteriostatic activity against
A. baumannii
, including strains resistant to imipenem.
Pharmacodynamics of Ceftazidime plus the Serine β-Lactamase Inhibitor AM-112 against
Escherichia coli
Containing TEM-1 and CTX-M-1 β-Lactamases
Authors: Bowker Karen E. , Noel Alan R. , Walsh Timothy R. , Rogers Chris A. , MacGowan Alasdair P. 
Published: October 2004

ABSTRACT

A strain of
Escherichia coli
containing TEM-1 and CTX-M-1 was tested in an in vitro pharmacokinetic model against ceftazidime with and without AM-112, a serine β-lactamase inhibitor. Ceftazidime alone was less effective than ceftazidime plus AM-112, and a single dose was more effective than three fractionated doses.
Nonisotopic, Semiautomated
Plasmodium falciparum
Bioassay for Measurement of Antimalarial Drug Levels in Serum or Plasma
Authors: Noedl Harald , Teja-Isavadharm Paktiya , Miller Robert Scott 
Published: October 2004

ABSTRACT

A simple, nonisotopic, semiautomated bioassay for the measurement of antimalarial drug levels in plasma or serum based on the quantitation of histidine-rich protein II in malaria culture is presented. The assay requires only small sample volumes and was found to be highly sensitive and reproducible. The results closely paralleled those obtained with isotopic bioassays (
R
= 0.988,
P
< 0.001) and high-performance liquid chromatography-electrochemical detection (
R
= 0.978,
P
< 0.001).
PERTURBATION TECHNIQUES FOR ON-CHIP LEARNING WITH ANALOGUE VLSI MLPs
Authors: CAIRNS GRAHAM , TARASSENKO LIONEL 
Published: October 2004

Microelectronic neural network technology has become sufficiently mature over the past few years that reliable performance can now be obtained from VLSI circuits under carefully controlled conditions (see Refs. 8 or 13 for example). The use of analogue VLSI allows low power, area efficient hardware realisations which can perform the computationally intensive feed-forward operation of neural networks at high speed, making real-time applications possible. In this paper we focus on important issues for the successful operation and implementation of on-chip learning with such analogue VLSI neural hardware, in particular the issue of weight precision. We first review several perturbation techniques which have been proposed to train multi-layer perceptron (MLP) networks. We then present a novel error criterion which performs well on benchmark problems and which allows simple integration of error measurement hardware for complete on-chip learning systems.