bluuebunny/crossref_metadata_2025_split huggingface dataset:
Electrolytic Generation of Oxygen Partially Explains Electrical Enhancement of Tobramycin Efficacy against
Pseudomonas aeruginosa
Biofilm
Authors: Stewart Philip S. , Wattanakaroon Wanida , Goodrum Lu , Fortun Susana M. , McLeod Bruce R. 
Published: October 2018

ABSTRACT

The role of electrolysis products, including protons, hydroxyl ions, reactive oxygen intermediates, oxygen, hydrogen, and heat, in mediating electrical enhancement of killing of
Pseudomonas aeruginosa
biofilms by tobramycin (the bioelectric effect) was investigated. The log reduction in biofilm viable cell numbers compared to the numbers for the untreated positive control effected by antibiotic increased from 2.88 in the absence of electric current to 5.58 in the presence of electric current. No enhancement of antibiotic efficacy was observed when the buffer composition was changed to simulate the reduced pH that prevails during electrolysis. Neither did stabilization of the pH during electrical treatment by increasing the buffer strength eliminate the bioelectric effect. The temperature increase measured in our experiments, less than 0.2°C, was far too small to account for the greatly enhanced antibiotic efficacy. The addition of sodium thiosulfate, an agent capable of rapidly neutralizing reactive oxygen intermediates, did not abolish electrical enhancement of killing. The bioelectric effect persisted when all of the ionic constituents of the medium except the two phosphate buffer components were omitted. This renders the possibility of electrochemical generation of an inhibitory ion, such as nitrite from nitrate, an unlikely explanation for electrical enhancement. The one plausible explanation for the bioelectric effect revealed by this study was the increased delivery of oxygen to the biofilm due to electrolysis. When gaseous oxygen was bubbled into the treatment chamber during exposure to tobramycin (without electric current), a 1.8-log enhancement of killing resulted. The enhancement of antibiotic killing by oxygen was not due simply to physical disturbances caused by sparging the gas because similar delivery of gaseous hydrogen caused no enhancement whatsoever.
Pharmacokinetics of the Antiviral Agent β-
d
-2′,3′-Didehydro-2′,3′-Dideoxy-5-Fluorocytidine in Rhesus Monkeys
Authors: Ma Li , Hurwitz Selwyn J. , Shi Junxing , McAtee Jeffrey J. , Liotta Dennis C. , McClure Harold M. , Schinazi Raymond F. 
Published: October 2018

ABSTRACT

The values of the pharmacokinetic parameters of the nucleoside antiretroviral agent β-
d
-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine (D-D4FC) in rhesus monkeys were determined with a two-compartment model after the administration of a single dose. The average values for the terminal half-life, renal clearance, and total systemic clearance for the intravenous administration route were 3.6 h and 0.31 and 0.43 liter · kg
−1
· h
−1
, respectively. The oral bioavailability of D-D4FC averaged 41%. For the intravenous administration route, 76% of the compound was recovered intact in the urine within 8 h, indicating that D-D4FC was eliminated mainly by renal excretion. D-D4FC was detected in the cerebrospinal fluid (CSF) at similar concentrations after administration by both the intravenous and oral routes. D-D4FC levels in plasma and CSF were higher than the median effective concentration for human immunodeficiency virus type 1 in vitro.
Interplay between Chromosomal β-Lactamase and the MexAB-OprM Efflux System in Intrinsic Resistance to β-Lactams in
Pseudomonas aeruginosa
Authors: Masuda Nobuhisa , Gotoh Naomasa , Ishii Chie , Sakagawa Eiko , Ohya Satoshi , Nishino Takeshi 
Published: October 2018

ABSTRACT

We investigated the role of chromosomal β-lactamase and the MexAB-OprM efflux system in intrinsic resistance to β-lactams in
Pseudomonas aeruginosa
. Determination of the susceptibilities of a series of isogenic mutants with impaired production of the β-lactamase and the efflux system to 16 β-lactams including penicillins, cephems, oxacephems, carbapenems, and a monobactam demonstrated that the intrinsic resistance of
P. aeruginosa
to most of the β-lactams is due to the interplay of both factors.
Carbapenem Activities against
Pseudomonas aeruginosa
: Respective Contributions of OprD and Efflux Systems
Authors: Köhler Thilo , Michea-Hamzehpour Mehri , Epp Simone F. , Pechere Jean-Claude 
Published: October 2018

ABSTRACT
While meropenem MICs were strongly influenced by the presence or absence of the MexAB-OprM efflux pump in both OprD-proficient and -deficient strain backgrounds, MICs of imipenem and of ER-35786 remained unchanged, demonstrating that meropenem is a substrate of MexAB-OprM but not imipenem and ER-35786. In vitro, all three carbapenems selected loss of OprD as a first mechanism of resistance. However, in an OprD-deficient background, meropenem was able to select MexAB-OprM overproducers as a secondary resistance mechanism, while ER-35786 selected a mutant cross-resistant to sparfloxacin and cefpirome.
Inhibition of Human Immunodeficiency Virus Type 1 Replication by Combination of Transcription Inhibitor K-12 and Other Antiretroviral Agents in Acutely and Chronically Infected Cells
Authors: Okamoto Mika , Okamoto Takashi , Baba Masanori 
Published: October 2018

ABSTRACT
8 - Difluoromethoxy - 1 - ethyl - 6 - fluoro - 1,4 - dihydro - 7 - [4 - (2 - methoxyphenyl) - 1 - piperazinyl] - 4 - oxoquinoline - 3 - carboxylic acid (K-12) has recently been identified as a potent and selective inhibitor of human immunodeficiency virus type 1 (HIV-1) transcription. In this study, we examined several combinations of K-12 and other antiretroviral agents for their inhibitory effects on HIV-1 replication in acutely and chronically infected cell cultures. Combinations of K-12 and a reverse transcriptase (RT) inhibitor, either zidovudine, lamivudine, or nevirapine, synergistically inhibited HIV-1 replication in acutely infected MT-4 cells. The combination of K-12 and the protease inhibitor nelfinavir (NFV) also synergistically inhibited HIV-1, whereas the synergism of this combination was weaker than that of the combinations with the RT inhibitors. K-12 did not enhance the cytotoxicities of RT and protease inhibitors. Synergism of the combinations was also observed in acutely infected peripheral blood mononuclear cells. The combination of K-12 and cepharanthine, a nuclear factor κB inhibitor, synergistically inhibited HIV-1 production in tumor necrosis factor alpha-stimulated U1 cells, a promonocytic cell line chronically infected with the virus. In contrast, additive inhibition was observed for the combination of K-12 and NFV. These results indicate that the combinations of K-12 and clinically available antiretroviral agents may have potential as chemotherapeutic modalities for the treatment of HIV-1 infection.
Effects of the Chinese Traditional Medicine Mao-Bushi-Saishin-To on Therapeutic Efficacy of a New Benzoxazinorifamycin, KRM-1648, againstMycobacterium aviumInfection in Mice
Authors: Shimizu Toshiaki , Tomioka Haruaki , Sato Katsumasa , Sano Chiaki , Akaki Tatsuya , Dekio Satoshi , Yamada Yoshitaka , Kamei Tsutomu , Shibata Hiroki , Higashi Natsumi 
Published: October 2018

ABSTRACTThe Chinese traditional medicine mao-bushi-saishin-to (MBST), which has anti-inflammatory effects and has been used to treat the common cold and nasal allergy in Japan, was examined for its effects on the therapeutic activity of a new benzoxazinorifamycin, KRM-1648 (KRM), againstMycobacterium aviumcomplex (MAC) infection in mice. In addition, we examined the effects of MBST on the anti-MAC activity of murine peritoneal macrophages (Mφs). First, MBST significantly increased the anti-MAC therapeutic activity of KRM when given to mice in combination with KRM, although MBST alone did not exhibit such effects. Second, MBST treatment of Mφs significantly enhanced the KRM-mediated killing of MAC bacteria residing in Mφs, although MBST alone did not potentiate the Mφ anti-MAC activity. MBST-treated Mφs showed decreased levels of reactive nitrogen intermediate (RNI) release, suggesting that RNIs are not decisive in the expression of the anti-MAC activity of such Mφ populations. MBST partially blocked the interleukin-10 (IL-10) production of MAC-infected Mφs without affecting their transforming growth factor β (TGF-β)-producing activity. Reverse transcription-PCR analysis of the lung tissues of MAC-infected mice at weeks 4 and 8 after infection revealed a marked increase in the levels of tumor necrosis factor alpha, gamma interferon (IFN-γ), IL-10, and TGF-β mRNAs. KRM treatment of infected mice tended to decrease the levels of the test cytokine mRNAs, except that it increased TGF-β mRNA expression at week 4. MBST treatment did not affect the levels of any cytokine mRNAs at week 8, while it down-regulated cytokine mRNA expression at week 4. At week 8, treatment of mice with a combination of KRM and MBST caused a marked decrease in the levels of the test cytokines mRNAs, especially IL-10 and IFN-γ mRNAs, although such effects were obscure at week 4. These findings suggest that down-regulation of the expression of IL-10 and TGF-β is related to the combined therapeutic effects of KRM and MBST against MAC infection.
Reduced Pyrazinamidase Activity and the Natural Resistance of
Mycobacterium kansasii
to the Antituberculosis Drug Pyrazinamide
Authors: Sun Zhonghe , Zhang Ying 
Published: October 2018

ABSTRACT

Pyrazinamide (PZA), an analog of nicotinamide, is a prodrug that requires conversion to the bactericidal compound pyrazinoic acid (POA) by the bacterial pyrazinamidase (PZase) activity of nicotinamidase to show activity against
Mycobacterium tuberculosis
. Mutations leading to a loss of PZase activity cause PZA resistance in
M. tuberculosis. M. kansasii
is naturally resistant to PZA and has reduced PZase activity along with an apparently detectable nicotinamidase activity. The role of the reduction in PZase activity in the natural PZA resistance of
M. kansasii
is unknown. The MICs of PZA and POA for
M. kansasii
were determined to be 500 and 125 μg/ml, respectively. Using [
14
C]PZA and [
14
C]nicotinamide, we found that
M. kansasii
had about 5-fold-less PZase activity and about 25-fold-less nicotinamidase activity than
M. tuberculosis
. The
M. kansasii pncA
gene was cloned on a 1.8-kb
Bam
HI DNA fragment, using
M. avium pncA
probe. Sequence analysis showed that the
M. kansasii pncA
gene encoded a protein with homology to its counterparts from
M. tuberculosis
(69.9%),
M. avium
(65.6%), and
Escherichia coli
(28.5%). Transformation of naturally PZA-resistant
M. bovis
BCG with
M. kansasii pncA
conferred partial PZA susceptibility. Transformation of
M. kansasii
with
M. avium pncA
caused functional expression of PZase and high-level susceptibility to PZA, indicating that the natural PZA resistance in
M. kansasii
results from a reduced PZase activity. Like
M. tuberculosis
,
M. kansasii
accumulated POA in the cells at an acidic pH; however, due to its highly active POA efflux pump, the naturally PZA-resistant species
M. smegmatis
did not. These findings suggest the existence of a weak POA efflux mechanism in
M. kansasii
.
Structure-Function Studies of Ser-289 in the Class C β-Lactamase from
Enterobacter cloacae
P99
Authors: Trépanier Sonia , Knox James R. , Clairoux Natalie , Sanschagrin François , Levesque Roger C. , Huletsky Ann 
Published: October 2018

ABSTRACT

Site-directed mutagenesis of Ser-289 of the class C β-lactamase from
Enterobacter cloacae
P99 was performed to investigate the role of this residue in β-lactam hydrolysis. This amino acid lies near the active site of the enzyme, where it can interact with the C-3 substituent of cephalosporins. Kinetic analysis of six mutant β-lactamases with five cephalosporins showed that Ser-289 can be substituted by amino acids with nonpolar or polar uncharged side chains without altering the catalytic efficiency of the enzyme. These data suggest that Ser-289 is not essential in the binding or hydrolytic mechanism of AmpC β-lactamase. However, replacement by Lys or Arg decreased by two- to threefold the
k
cat
of four of the five β-lactams tested, particularly cefoperazone, cephaloridine, and cephalothin. Three-dimensional models of the mutant β-lactamases revealed that the length and positive charge of the side chain of Lys and Arg could create an electrostatic linkage to the C-4 carboxylic acid group of the dihydrothiazine ring of the acyl intermediate which could slow the deacylation step or hinder release of the product.
Comparative Study of the Anti-Human Cytomegalovirus Activities and Toxicities of a Tetrahydrofuran Phosphonate Analogue of Guanosine and Cidofovir
Authors: Bedard Jean , May Suzanne , Lis Martin , Tryphonas Leander , Drach John , Huffman John , Sidwell Robert , Chan Laval , Bowlin Terry , Rando Robert 
Published: October 2018

ABSTRACT

Cidofovir is the first nucleoside monophosphate analogue currently being used for the treatment of human cytomegalovirus (HCMV) retinitis in individuals with AIDS. Unfortunately, the period of therapy with the use of this compound may be limited due to the possible emergence of serious irreversible nephrotoxic effects. New drugs with improved toxicity profiles are needed. The goal of this study was to investigate the anticytomegaloviral properties and drug-induced toxicity of a novel phosphonate analogue, namely, (−)-2-(
R
)-dihydroxyphosphinoyl-5-(
S
)-(guanin-9′-yl-methyl) tetrahydrofuran (compound 1), in comparison with those of cidofovir. The inhibitory activities of both compounds on HCMV propagation in vitro were similar against the AD 169 and Towne strains, with 50% inhibitory concentrations ranging from 0.02 to 0.17 μg/ml for cidofovir and <0.05 to 0.09 μg/ml for compound 1. A clinical HCMV isolate that was resistant to ganciclovir and that had a known mutation within the UL54 DNA polymerase gene and a cidofovir-resistant laboratory strain derived from strain AD 169 remained sensitive to compound 1, whereas their susceptibilities to ganciclovir and cidofovir were reduced by 33- and 10-fold, respectively. Both compound 1 and cidofovir exhibited equal potencies in an experimentally induced murine cytomegalovirus (MCMV) infection in mice, with a prevention or prolongation of mean day to death at dosages of 1.0, 3.2, and 10.0 mg/kg of body weight/day. In cytotoxicity experiments, compound 1 was found to be generally more toxic than cidofovir in cell lines Hs68, HFF, and 3T3-L1 (which are permissive for HCMV or MCMV replication) but less toxic than cidofovir in MRC-5 cells (which are permissive for HCMV replication). Drug-induced toxic side effects were noticed for both compounds in rats and guinea pigs in a 5-day repeated-dose study. In guinea pigs, a greater weight loss was noticed with cidofovir than with compound 1 at dosages of 3.0 and 10.0 mg/kg/day. An opposite effect was detected in rats, which were treated with the compounds at relatively high dosages (up to 100 mg/kg/day). Compound 1 and cidofovir were nephrotoxic in both rats and guinea pigs, with the epithelium lining the proximal convoluted tubules in the renal cortex being the primary target site. The incidence and the severity of the lesions were found to be dose dependent. The lesions observed were characterized by cytoplasm degeneration and nuclear modifications such as karyomegaly, the presence of pseudoinclusions, apoptosis, and degenerative changes. In the guinea pig model, a greater incidence and severity of lesions were observed for cidofovir than for compound 1 (
P
< 0.001) with a drug regimen of 10 mg/kg/day.
A Multiple Drug Interaction Study of Stavudine with Agents for Opportunistic Infections in Human Immunodeficiency Virus-Infected Patients
Authors: Piscitelli Stephen C. , Kelly Grace , Walker Robert E. , Kovacs Joseph , Falloon Judith , Davey Richard T. , Raje Sangita , Masur Henry , Polis Michael A. 
Published: October 2018

ABSTRACT

The effects of multiple opportunistic infection medications on stavudine pharmacokinetics were evaluated. Ten patients with CD4 counts of less than 200 cells/mm
3
received stavudine (40 mg twice daily) in combination with one to three other drugs used to treat opportunistic infections. Serial blood samples for stavudine concentrations were collected after 1 week of therapy on each regimen and assayed for stavudine by using a validated high-pressure liquid chromatography method. Although the maximum concentration of drug in serum was significantly decreased when the drug was given in combination with three opportunistic infection medications, the area under the concentration-time curve did not significantly differ across various treatment regimens. Stavudine exposure was not significantly altered by multiple concomitant medications. Side effects were minor throughout the 3-month study period. The tolerability of stavudine, combined with its lack of drug interactions, makes it an attractive agent for use as part of a combination regimen.
Ketolide Treatment of
Haemophilus influenzae
Experimental Pneumonia
Authors: Piper Kerryl E. , Rouse Mark S. , Steckelberg James M. , Wilson Walter R. , Patel Robin 
Published: October 2018

ABSTRACT

The MICs of HMR 3004 and HMR 3647 at which 90% of beta-lactamase-producing
Haemophilus influenzae
isolates were inhibited were 4 and 2 μg/ml, respectively. Both HMR 3004 and HMR 3647 were active against beta-lactamase-producing
H. influenzae
in a murine model of experimental pneumonia. As assessed by pulmonary clearance of
H. influenzae
, HMR 3004 was more effective (
P
< 0.05) than was azithromycin, ciprofloxacin, clarithromycin, erythromycin A, pristinamycin, or HMR 3647 in this model.
Protection by Short-Chain Fatty Acids against 1-β-
d
-Arabinofuranosylcytosine-Induced Intestinal Lesions in Germfree Mice
Authors: Ramos Mariana Gontijo , Bambirra Eduardo Alves , Nicoli Jacques Robert , Cara Denise Carmona , Vieira Enio Cardillo , Alvarez-Leite Jacqueline 
Published: October 2018

ABSTRACT

In germfree mice, the administration of short-chain fatty acids (SCFA) protected the intestinal mucosa from damage produced by 1-β-
d
-arabinofuranosylcytosine (Ara-C). Animals receiving SCFA and Ara-C had intestinal morphologies closer to normal than the control animals, which had severe intestinal lesions. We concluded that orally administrated SCFA reduce intestinal lesions, improving the mucosa pattern of the small intestine and colon.
Pharmacodynamic Effects of Subinhibitory Concentrations of Rufloxacin on Bacterial Virulence Factors
Authors: Braga Pier Carlo , Sala Maria Teresa , dal Sasso Monica 
Published: October 2018

ABSTRACT

It has been reported that subinhibitory concentrations (sub-MICs) of some fluoroquinolones are still capable of affecting the topological characteristics of DNA (inhibition DNA-gyrase) and that this leads to a reduction in some of the factors responsible for bacterial virulence (by means of the disruption of protein synthesis and alterations in phenotype expression), even though the microorganisms themselves are not killed. The present study investigated the ability of sub-MICs of rufloxacin, an orally absorbed monofluorinated quinolone with a long half-life (28 to 30 h), to interfere with the bacterial virulence parameters of adhesiveness, hemagglutination, hydrophobicity, motility, and filamentation, as well as their interactions with host neutrophilic defenses such as phagocytosis, killing, and oxidative bursts. It was observed that
Escherichia coli
adhesiveness was significantly reduced at rufloxacin concentrations of 1/32 MIC, hemagglutination and hydrophobicity were significantly reduced at concentrations of, respectively, 1/4 MIC and 1/8 MIC, and motility was significantly reduced at concentrations of 1/16 MIC; filamentation was still present at concentrations of 1/4 MIC. Phagocytosis was not affected, but killing significantly increased from 1/2 MIC to 1/8 MIC; oxidative bursts measured by means of chemiluminescence were not affected. The fact that sub-MICs are still effective in interfering with the parameters of bacterial virulence is useful information that needs to be correlated with pharmacokinetic data in order to extend our knowledge of the most effective concentrations that can be used to optimize treatment schedules, for example, single administrations, particularly in noncomplicated lower urinary tract infections.
Effectiveness and Toxicity of Gentamicin in an Experimental Model of Pyelonephritis: Effect of the Time of Administration
Authors: LeBrun Michel , Grenier Louis , Gourde Pierrette , Bergeron Michel G. , Labrecque Gaston , Beauchamp Denis 
Published: October 2018

ABSTRACT

Temporal variations in the renal toxicity of aminoglycosides have been reported for experimental animals as well as for humans. In fact, maximal renal toxicity of aminoglycosides was observed when the drug was given during the rest period, while a lower toxicity was observed when the drug was injected during the activity period. The aim of the present study was to evaluate temporal variations in the effectiveness and renal toxicity of gentamicin in an experimental model of pyelonephritis in rats. The experiments were carried out with female Sprague-Dawley rats (185 to 250 g). They had free access to food and water throughout the study and were maintained on a 14-h light–10-h dark cycle. Animals were divided into four groups corresponding to the respective time of induction of pyelonephritis and treatment: 0700, 1300, 1900, and 0100 h. Pyelonephritis was induced by a direct inoculation of
Escherichia coli
(10
7
to 10
8
CFU) in the left kidney. Animals were treated for 3 and 7 days with a single daily dose of gentamicin (20 and 40 mg/kg of body weight, respectively) or saline (NaCl, 0.9%) at either 0700, 1300, 1900, or 0100 h. Animals treated at 0100 h for 3 days with gentamicin (20 mg/kg) showed a significantly lower number of bacteria in their kidneys than did all other groups (
P
< 0.01). After 7 days of treatment, the efficacy, evaluated by the log CFU per gram of tissue and by the percentage of sterilized kidneys, was also higher when gentamicin was administered at 0100 h. The β-galactosidase and the
N
-acetyl-β-
d
-glucosaminidase activities were significantly higher in urine of rats given gentamicin at 1300 h than in urine of rats treated at another time of day (
P
< 0.05). Gentamicin injected at 1300 h induced a significantly greater increase of [
3
H]thymidine incorporation into DNA of renal cortex (
P
< 0.01), a significantly greater inhibition of sphingomyelinase activity (
P
< 0.05), and significantly more histopathological lesions than the same dose injected at another time of the day. Creatinine and blood urea nitrogen levels in serum were significantly higher (
P
< 0.05) and the creatinine clearance was significantly lower (
P
< 0.05) when gentamicin was injected at 1300 h than when it was injected at another time of day. Our data suggest temporal variations in both the toxicity and the effectiveness of gentamicin, the drug being more effective and less toxic when injected during the activity period of the animals.