bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selective Inhibition of Human Papillomavirus-Induced Cell Proliferation by (
S
)-1-[3-Hydroxy-2-(Phosphonylmethoxy)propyl]cytosine
Authors: Johnson J. A. , Gangemi J. D. 
Published: October 2018

ABSTRACT

(
S
)-1-[3-Hydroxy-2-(phosphonylmethoxy)propyl]cytosine (HPMPC) is a nucleoside phosphonate analog which in its active diphosphorylated form is known to inhibit herpesvirus DNA polymerase. In this study, we have demonstrated that, in a dose-dependent manner, this compound irreversibly suppressed proliferation of cells infected with human papillomavirus (HPV), which does not possess a viral DNA polymerase. To elucidate the mechanism of cell growth inhibition, cell cycle indicator-regulator expression, thymidine incorporation, transcript levels of apoptosis factors, and anabolic products of HPMPC following drug treatment were evaluated. HPMPC treatment reduced WAF1 (p21) levels independent of those of p53, while proliferating cell nuclear antigen increased. However, in comparison to controls, HPMPC-treated cells displayed a decrease in thymidine incorporation, indicating an inhibition of host DNA polymerase activity. In normal primary keratinocytes, HPMPC predominantly accumulated in the form of the choline adduct HPMPCp-choline. However, in HPV type 16-transformed keratinocytes, HPMPCpp was the most abundant anabolic product, with little HPMPCp-choline having formed. The data imply that an unrecognized viral factor is modulating the conversion of nucleotides, including HPMPC, to the triphosphorylated form.
Genes Specific for the Biosynthesis of Clavam Metabolites Antipodal to Clavulanic Acid Are Clustered with the Gene for Clavaminate Synthase 1 in
Streptomyces clavuligerus
Authors: Mosher Roy H. , Paradkar Ashish S. , Anders Cecilia , Barton Barry , Jensen Susan E. 
Published: October 2018

ABSTRACT

Portions of the
Streptomyces clavuligerus
chromosome flanking
cas1
, which encodes the clavaminate synthase 1 isoenzyme (CAS1), have been cloned and sequenced. Mutants of
S. clavuligerus
disrupted in
cvm1
, the open reading frame located immediately upstream of
cas1
, were constructed by a gene replacement procedure. Similar techniques were used to generate
S. clavuligerus
mutants carrying a deletion that encompassed portions of the two open reading frames,
cvm4
and
cvm5
, located directly downstream of
cas1
. Both classes of mutants still produced clavulanic acid and cephamycin C but lost the ability to synthesize the antipodal clavam metabolites clavam-2-carboxylate, 2-hydroxymethyl-clavam, and 2-alanylclavam. These results suggested that
cas1
is clustered with genes essential and specific for clavam metabolite biosynthesis. When a
cas1
mutant of
S. clavuligerus
was constructed by gene replacement, it produced lower levels of both clavulanic acid and most of the antipodal clavams except for 2-alanylclavam. However, a double mutant of
S. clavuligerus
disrupted in both
cas1
and
cas2
produced neither clavulanic acid nor any of the antipodal clavams, including 2-alanylclavam. This outcome was consistent with the contribution of both CAS1 and CAS2 to a common pool of clavaminic acid that is shunted toward clavulanic acid and clavam metabolite biosynthesis.
In Vitro Susceptibilities of Clinical Yeast Isolates to the New Antifungal Eberconazole Compared with Their Susceptibilities to Clotrimazole and Ketoconazole
Authors: Torres-Rodríguez Josep M. , Mendez Raúl , López-Jodra Olga , Morera Yolanda , Espasa Mateu , Jimenez Teresa , Lagunas Carme 
Published: October 2018

ABSTRACT

The antifungal activity of eberconazole, a new imidazole derivative, against 124 clinical isolates of
Candida
comprising eight different species and to 34 isolates of
Cryptococcus neoformans
was compared to those of clotrimazole and ketoconazole. MICs of eberconazole, determined by the National Committee for Clinical Laboratory Standards standardized microbroth method, were equal to or lower than those of other azoles, especially for
Candida krusei
and
Candida glabrata
, which are usually resistant to triazoles.
Molecular Investigation of the Postantibiotic Effects of Clarithromycin and Erythromycin on
Staphylococcus aureus
Cells
Authors: Champney W. Scott , Tober Craig L. 
Published: October 2018

ABSTRACT

The kinetics of recovery after inhibition of growth by erythromycin and clarithromycin were examined in
Staphylococcus aureus
cells. After inhibition for one mass doubling by 0.5 μg of the antibiotics/ml, a postantibiotic effect (PAE) of 3 and 4 h duration was observed for the two drugs before growth resumed. Cell viability was reduced by 25% with erythromycin and 45% with clarithromycin compared with control cells. Erythromycin and clarithromycin treatment reduced the number of 50S ribosomal subunits to 24 and 13% of the number found in untreated cells. 30S subunit formation was not affected. Ninety minutes was required for resynthesis to give the control level of 50S particles. Protein synthesis rates were diminished for up to 4 h after the removal of the macrolides. This continuing inhibition of translation was the result of prolonged binding of the antibiotics to the 50S subunit as measured by
14
C-erythromycin binding to ribosomes in treated cells. The limiting factors in recovery from macrolide inhibition in these cells, reflected as a PAE, are the time required for the synthesis of new 50S subunits and the slow loss of the antibiotics from ribosomes in inhibited cells.
Antimicrobial Activities of Amine- and Guanidine-Functionalized Cholic Acid Derivatives
Authors: Li Chunhong , Lewis Matthew R. , Gilbert Amy B. , Noel Mark D. , Scoville David H. , Allman Glenn W. , Savage Paul B. 
Published: October 2018

ABSTRACT
Compounds in a series of cholic acid derivatives, designed to mimic the activities of polymyxin B and its derivatives, act as both potent antibiotics and effective permeabilizers of the outer membranes of gram-negative bacteria. Some of these compounds rival polymyxin B in antibacterial activity against gram-negative bacteria and are also very active against gram-positive organisms. Other compounds interact synergistically with hydrophobic antibiotics to inhibit bacterial growth.
In Vitro Antifungal Activity of Nikkomycin Z in Combination with Fluconazole or Itraconazole
Authors: Li R. K. , Rinaldi M. G. 
Published: October 2018

ABSTRACT

Nikkomycins are nucleoside-peptide antibiotics produced by
Streptomyces
species with antifungal activities through the inhibition of chitin synthesis. We investigated the antifungal activities of nikkomycin Z alone and in combination with fluconazole and itraconazole. Checkerboard synergy studies were carried out by a macrobroth dilution procedure with RPMI 1640 medium at pH 6.0. At least 10 strains of the following fungi were tested:
Candida albicans
, other
Candida
spp.,
Cryptococcus neoformans
,
Coccidioides immitis
,
Aspergillus
spp., and dematiacious fungi (including
Exophiala jeanselmei
,
Exophiala spinifera
,
Bipolaris spicifera
,
Wangiella dermatitidis
,
Ochroconis humicola
,
Phaeoannellomyces werneckii
, and
Cladophialophora bantiana
), and 2 strains each of
Fusarium
,
Scedosporium
,
Paecilomyces
,
Penicillium
, and
Trichoderma
spp. A total of 110 isolates were examined. Inocula of fungal elements were standardized by hemacytometer counting or spectrophotometrically. MICs and minimum lethal concentrations (MLCs) were determined visually by comparison of growth in drug-treated tubes with growth in drug-free control tubes. Additive and synergistic interactions between nikkomycin and either fluconazole or itraconazole were observed against
C. albicans
,
Candida parapsilosis
,
Cryptococcus neoformans
, and
Coccidioides immitis
. Marked synergism was also observed between nikkomycin and itraconazole against
Aspergillus fumigatus
and
Aspergillus flavus
. No antagonistic interaction between the drugs was observed with any of the strains tested.
Subpopulations of
Helicobacter pylori
Are Responsible for Discrepancies in the Outcome of Nitroimidazole Susceptibility Testing
Authors: van der Wouden E. J. , de Jong A. , Thijs J. C. , Kleibeuker J. H. , van Zwet A. A. 
Published: October 2018

ABSTRACT

Metronidazole susceptibility testing by E test was compared to that by disk diffusion for 263
Helicobacter pylori
isolates and to that by breakpoint agar dilution for 90
H. pylori
isolates. In 5% and 6% of the cases, respectively, results were discrepant. For each of 52 clinical isolates an E test was performed on 10 separate colonies. Subpopulations of resistant and susceptible bacteria were found in five cases. From three isolates, each colony was subcultured and tested up to 10 times. All but 1 of 292 tests showed the same result. We conclude that the E test is reliable and that subpopulations are responsible for discordant results.
In Vitro Anti-Human Immunodeficiency Virus Activities of
Z
- and
E
-Methylenecyclopropane Nucleoside Analogues and Their Phosphoro-
l
-Alaninate Diesters
Authors: Uchida Hiroyuki , Kodama Eiichi N. , Yoshimura Kazuhisa , Maeda Yosuke , Kosalaraksa Pope , Maroun Victor , Qiu Yao-Ling , Zemlicka Jiri , Mitsuya Hiroaki 
Published: October 2018

ABSTRACT

Nucleoside analogues with a
Z
- or an
E
-methylenecyclopropane moiety were synthesized and examined for activity against human immunodeficiency virus type 1 (HIV-1) in vitro. The addition of a methyl phenyl phosphoro-
l
-alaninate moiety to modestly active analogues resulted in potentiation of their anti-HIV-1 activity. Two such compounds, designated QYL-685 (with 2,6-diaminopurine) and QYL-609 (with adenine), were most potent against HIV-1 in vitro, with 50% inhibitory concentrations of 0.034 and 0.0026 μM, respectively, in MT-2 cell-based assays. Both compounds were active against zidovudine-resistant, didanosine-resistant, and multi-dideoxynucleoside-resistant infectious clones in vitro. Further development of these analogues as potential therapies for HIV-1 infection is warranted.
Pharmacokinetic-Pharmacodynamic Contributions to the Convulsant Activity of Fluoroquinolones in Rats
Authors: Delon Annie , Bouquet Serge , Huguet Francois , Brunet Valerie , Courtois Philippe , Couet William 
Published: October 2018

ABSTRACT
The in vivo convulsant activities in rats of five representative fluoroquinolones (FQs), norfloxacin, enoxacin, sparfloxacin, fleroxacin, and pefloxacin, were compared. The experimental approach allowed distinction between the drugs’ ability to reach the pharmacological receptors at the level of the central nervous system (pharmacokinetic contribution) and their ability to interact with these receptors (pharmacodynamic contribution). The presence of a methyl group on the piperazine moiety decreased the pharmacodynamic contribution to the convulsant activity by severalfold, and the ratios of concentrations of the FQs in cerebrospinal fluid (CSF) to concentrations of unbound FQs in plasma varied from about 5 to 75% as a function of lipophilicity. Interestingly, FQs with the highest intrinsic convulsant activities had the lowest levels of diffusion in CSF and vice versa. This in vivo approach provides information complementary to that of in vitro experiments and should be recommended for early preclinical assessment of a new FQ’s epileptogenic risk.
Nomenclature for New Tetracycline Resistance Determinants
Authors: Levy Stuart B. , McMurry Laura M. , Barbosa Teresa M. , Burdett Vickers , Courvalin Patrice , Hillen Wolfgang , Roberts Marilyn C. , Rood Julian I. , Taylor Diane E. 
Published: October 2018

ABSTRACT
Letters of the English alphabet have heretofore been used to name tetracycline resistance determinants. Since all 26 letters have now been used, a nomenclature employing numerals is recommended for future determinants, and one laboratory has offered to coordinate the assignment of numerals.
Safety and Efficacy of Intravenous Zanamivir in Preventing Experimental Human Influenza A Virus Infection
Authors: Calfee David P. , Peng Amy W. , Cass Lindsey M. , Lobo Monica , Hayden Frederick G. 
Published: October 2018

ABSTRACT

Zanamivir is a potent inhibitor of influenza A and B virus neuraminidases and is active topically in experimental and natural human influenza. We conducted this double-blinded, placebo-controlled study to evaluate the safety and efficacy of intravenously administered zanamivir. Susceptible volunteers were randomized to receive either saline or zanamivir (600 mg) intravenously twice daily for 5 days beginning 4 h prior to intranasal inoculation with ∼10
5
50% tissue culture infectious doses (TCID
50
) of influenza A/Texas/36/91 (H1N1) virus. Reductions in the frequency of viral shedding (0% versus 100% in placebo,
P
< 0.005) and seroconversion (14% versus 100% in placebo,
P
< 0.005) and decreases in viral titer areas under the curve (0 versus 11.6 [median] log
10
TCID
50
· day/ml in placebo,
P
< 0.005) were observed in the zanamivir group, as were reductions in fever (14% versus 88% in placebo,
P
< 0.05), upper respiratory tract illness (0% versus 100% in placebo,
P
< 0.005), total symptom scores (1 versus 44 [median] in placebo,
P
< 0.005), and nasal-discharge weight (3.9 g versus 17.5 g [median] in placebo,
P
< 0.005). Zanamivir was detectable in nasal lavage samples collected on days 2 and 4 (unadjusted median concentrations, 10.5 and 12.0 ng/ml of nasal wash, respectively). This study demonstrates that intravenously administered zanamivir is distributed to the respiratory mucosa and is protective against infection and illness following experimental human influenza A virus inoculation.
Molecular Characterization of TEM-59 (IRT-17), a Novel Inhibitor-Resistant TEM-Derived β-Lactamase in a Clinical Isolate of
Klebsiella oxytoca
Authors: Bermudes H. , Jude F. , Chaibi E. B. , Arpin C. , Bebear C. , Labia R. , Quentin C. 
Published: October 2018

ABSTRACT

A clinical isolate of
Klebsiella oxytoca
(Kox 443) was found to have a low-level resistance to broad-spectrum penicillins (MICs of amoxicillin and ticarcillin, 256 and 32 μg/ml, respectively), without substantial potentiation by 2 μg of clavulanic acid per ml (amoxicillin- and ticarcillin-clavulanate, 128 and 8 μg/ml, respectively), while being fully susceptible to cephalosporins and other β-lactam antibiotics. These resistances were carried by a ca. 50-kb conjugative plasmid that encodes a single β-lactamase with a pI of 5.6. Compared to TEM-2, this enzyme exhibited a 3- to 30-fold higher

K
m

and a decreased maximal hydrolysis rate for β-lactams; higher concentrations of suicide inactivators (5- to 500-fold higher concentrations giving a 50% reduction in hydrolysis) were required for inhibition. Nucleotide sequence analysis revealed identity between the
bla
TEM
gene of Kox 443 and the
bla
TEM-2
gene, except for a single A-to-G change at position 590, leading to the amino acid change from Ser-130 Gly. This mutation has not been reported previously in the TEM type β-lactamases produced by clinical strains, and the novel enzyme was called TEM-59 (alternative name IRT-17). This is the first description of an inhibitor-resistant TEM-derived enzyme in the species
K. oxytoca.
Nonactin Biosynthesis: the Product of
nonS
Catalyzes the Formation of the Furan Ring of Nonactic Acid
Authors: Woo Anton J. , Strohl William R. , Priestley Nigel D. 
Published: October 2018

ABSTRACT

Nonactin is the parent compound of a group of ionophore antibiotics, known as the macrotetrolides, produced by
Streptomyces griseus
subsp.
griseus
ETH A7796. Nonactin is a significant compound because of its inhibitory effects on the P170 glycoprotein-mediated efflux of chemotherapeutic agents in multiple-drug-resistant cancer cells. Nonactin is also significant in that it is a highly atypical polyketide. Very little is presently known about the genes of the nonactin biosynthesis cluster. In this paper we describe our efforts to establish a connection between the product of a gene from the nonactin biosynthesis cluster and a known biochemical transformation in nonactin biosynthesis. Nonactate synthase is the enzyme which catalyzes the formation of nonactic acid from an acyclic precursor in nonactin biosynthesis. We have synthesized the substrate for this enzyme and have detected the in vitro cyclization activity of the substrate in cell-free preparations of
S. griseus
subsp.
griseus
ETH A7796. Previous studies by R. Plater and J. A. Robinson (Gene 112:117–122, 1992) had suggested, based on sequence homology, that the product of a partial open reading frame found close to the tetranactin resistance gene of
S. griseus
could be the nonactate synthase. We have therefore cloned, sequenced, and heterologously expressed this full gene (
nonS
), and we have shown that the gene product, NonS, does indeed catalyze the formation of the furan ring of nonactic acid as hypothesized.
Lysostaphin Treatment of Experimental Aortic Valve Endocarditis Caused by a
Staphylococcus aureus
Isolate with Reduced Susceptibility to Vancomycin
Authors: Patron Roberto L. , Climo Michael W. , Goldstein Beth P. , Archer Gordon L. 
Published: October 2018

ABSTRACT

The rabbit model of endocarditis was used to test the effectiveness of vancomycin and two different lysostaphin dosing regimens for the treatment of infections caused by a
Staphylococcus aureus
strain with reduced susceptibility to vancomycin (glycopeptide-intermediate susceptible
S. aureus
[GISA]). Vancomycin was ineffective, with no evidence of sterilization of aortic valve vegetations. However, rates of sterilization of aortic valve vegetations were significantly better for animals treated with either a single dose of lysostaphin (43%) or lysostaphin given twice daily for 3 days (83%) than for animals treated with vancomycin. Rabbits given a single dose of lysostaphin followed by a 3-day drug-free period had mean reductions in aortic valve vegetation bacterial counts of 7.27 and 6.63 log
10
CFU/g compared with those for untreated control rabbits and the vancomycin-treated group, respectively. We conclude that lysostaphin is an effective alternative for the treatment of experimental aortic valve endocarditis caused by a clinical VISA strain.
In Vitro Activities of the Everninomicin SCH 27899 and Other Newer Antimicrobial Agents against
Borrelia burgdorferi
Authors: Dever Lisa L. , Torigian Christine V. , Barbour Alan G. 
Published: October 2018

ABSTRACT

The in vitro activity of the everninomicin antibiotic SCH 27899 against 17 isolates of
Borrelia
spp. was investigated. MICs ranged from 0.06 to 0.5 μg/ml. Time-kill studies with the B31 strain of
B. burgdorferi
demonstrated ≥3-log
10
-unit killing after 72 h with concentrations representing four times the MIC. The in vitro activity of four other newer antimicrobial agents, meropenem, cefepime, quinupristin-dalfopristin, and linezolid, was also tested against the B31 strain. Meropenem was the most potent of the latter agents, with an MIC of 0.125 μg/ml.
Improvement of In Vitro and In Vivo Antileishmanial Activities of 2′,6′-Dihydroxy-4′-Methoxychalcone by Entrapment in Poly(
d,l
-Lactide) Nanoparticles
Authors: Torres-Santos Eduardo Caio , Rodrigues José M. , Moreira Davyson L. , Kaplan Maria Auxiliadora C. , Rossi-Bergmann Bartira 
Published: October 2018

ABSTRACT

The inhibition of intracellular
Leishmania amazonensis
growth by 2′,6′-dihydroxy-4′-methoxychalcone (DMC) isolated from
Piper aduncum
was further enhanced after encapsulation of DMC in polymeric nanoparticles. Encapsulated DMC also showed increased antileishmanial activity in infected BALB/c mice, as evidenced by significantly smaller lesions and fewer parasites in the lesions.
Identification of a Novel β-Lactamase Produced by
Xanthomonas campestris
, a Phytopathogenic Bacterium
Authors: Weng Shu-Fen , Chen Chun-Yi , Lee Yeong-Sheng , Lin Juey-Wen , Tseng Yi-Hsiung 
Published: October 2018

ABSTRACT

The
Xanthomonas campestris
pv. campestris 11 chromosome encodes a periplasmic β-lactamase of 30 kDa. Gene replacement and complementation confirmed the presence of this enzyme. Its deduced amino acid sequence shows identity and conserved domains between it and
Stenotrophomonas maltophilia
L2 and other Ambler class A/Bush group 2 β-lactamases. Southern hybridization detected a single homologous fragment in each of 12 other
Xanthomonas
strains, indicating that the presence of a β-lactamase gene is common among xanthomonads.
Unique Anti-Human Immunodeficiency Virus Activities of the Nonnucleoside Reverse Transcriptase Inhibitors Calanolide A, Costatolide, and Dihydrocostatolide
Authors: Buckheit Robert W. , White E. Lucile , Fliakas-Boltz Valerie , Russell Julie , Stup Tracy L. , Kinjerski Tracy L. , Osterling Mark C. , Weigand Ann , Bader John P. 
Published: October 2018

ABSTRACT

(+)-Calanolide A (NSC 650886) has previously been reported to be a unique and specific nonnucleoside inhibitor of the reverse transcriptase (RT) of human immunodeficiency virus (HIV) type 1 (HIV-1) (M. J. Currens et al., J. Pharmacol. Exp. Ther., 279:645–651, 1996). Two isomers of calanolide A, (−)-calanolide B (NSC 661122; costatolide) and (−)-dihydrocalanolide B (NSC 661123; dihydrocostatolide), possess antiviral properties similar to those of calanolide A. Each of these three compounds possesses the phenotypic properties ascribed to the pharmacologic class of nonnucleoside RT inhibitors (NNRTIs). The calanolide analogs, however, exhibit 10-fold enhanced antiviral activity against drug-resistant viruses that bear the most prevalent NNRTI resistance that is engendered by amino acid change Y181C in the RT. Further enhancement of activity is observed with RTs that possess the Y181C change together with mutations that yield resistance to AZT. In addition, enzymatic inhibition assays have demonstrated that the compounds inhibit RT through a mechanism that affects both the

K
m

for dTTP and the
V
max
, i.e., mixed-type inhibition. In fresh human cells, costatolide and dihydrocostatolide are highly effective inhibitors of low-passage clinical virus strains, including those representative of the various HIV-1 clade strains, syncytium-inducing and non-syncytium-inducing isolates, and T-tropic and monocyte-tropic isolates. Similar to calanolide A, decreased activities of the two isomers were observed against viruses and RTs with amino acid changes at residues L100, K103, T139, and Y188 in the RT, although costatolide exhibited a smaller loss of activity against many of these NNRTI-resistant isolates. Comparison of cross-resistance data obtained with a panel of NNRTI-resistant virus strains suggests that each of the three stereoisomers may interact differently with the RT, despite their high degree of structural similarity. Selection of viruses resistant to each of the three compounds in a variety of cell lines yielded viruses with T139I, L100I, Y188H, or L187F amino acid changes in the RT. Similarly, a variety of resistant virus strains with different amino acid changes were selected in cell culture when the calanolide analogs were used in combination with other active anti-HIV agents, including nucleoside and nonnucleoside RT and protease inhibitors. In assays with combinations of anti-HIV agents, costatolide exhibited synergy with these anti-HIV agents. The calanolide isomers represent a novel and distinct subgroup of the NNRTI family, and these data suggest that a compound of the calanolide A series, such as costatolide, should be evaluated further for therapeutic use in combination with other anti-HIV agents.