bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Vitro and In Vivo Antibacterial Activities of a Novel Glycylcycline, the 9-
t
-Butylglycylamido Derivative of Minocycline (GAR-936)
Authors: Petersen P. J. , Jacobus N. V. , Weiss W. J. , Sum P. E. , Testa R. T. 
Published: October 2018

ABSTRACT

The 9-
t
-butylglycylamido derivative of minocycline (TBG-MINO) is a recently synthesized member of a novel group of antibiotics, the glycylcyclines. This new derivative, like the first glycylcyclines, the
N
,
N
-dimethylglycylamido derivative of minocycline and 6-demethyl-6-deoxytetracycline, possesses activity against bacterial isolates containing the two major determinants responsible for tetracycline resistance: ribosomal protection and active efflux. The in vitro activities of TBG-MINO and the comparative agents were evaluated against strains with characterized tetracycline resistance as well as a spectrum of recent clinical aerobic and anaerobic gram-positive and gram-negative bacteria. TBG-MINO, with an MIC range of 0.25 to 0.5 μg/ml, showed good activity against strains expressing
tet
(M) (ribosomal protection),
tet
(A),
tet
(B),
tet
(C),
tet
(D), and
tet
(K) (efflux resistance determinants). TBG-MINO exhibited similar activity against methicillin-resistant
Staphylococcus aureus
(MRSA), penicillin-resistant streptococci, and vancomycin-resistant enterococci (MICs at which 90% of strains are inhibited, ≤0.5 μg/ml). TBG-MINO exhibited activity against a wide diversity of gram-negative aerobic and anaerobic bacteria, most of which were less susceptible to tetracycline and minocycline. The in vivo protective effects of TBG-MINO were examined against acute lethal infections in mice caused by
Escherichia coli
,
S. aureus
, and
Streptococcus pneumoniae
isolates. TBG-MINO, administered intravenously, demonstrated efficacy against infections caused by
S. aureus
including MRSA strains and strains containing
tet
(K) or
tet
(M) resistance determinants (median effective doses [ED
50
s], 0.79 to 2.3 mg/kg of body weight). TBG-MINO demonstrated efficacy against infections caused by tetracycline-sensitive
E. coli
strains as well as
E. coli
strains containing either
tet
(M) or the efflux determinant
tet
(A),
tet
(B), or
tet
(C) (ED
50
s, 1.5 to 3.5 mg/kg). Overall, TBG-MINO shows antibacterial activity against a wide spectrum of gram-positive and gram-negative aerobic and anaerobic bacteria including strains resistant to other chemotherapeutic agents. The in vivo protective effects, especially against infections caused by resistant bacteria, corresponded with the in vitro activity of TBG-MINO.
Bile Salts: Natural Detergents for the Prevention of Sexually Transmitted Diseases
Authors: Herold Betsy C. , Kirkpatrick Risa , Marcellino Daniel , Travelstead Anna , Pilipenko Valentina , Krasa Holly , Bremer James , Dong Li Jin , Cooper Morris D. 
Published: October 2018

ABSTRACTThe development of new, safe, topical microbicides for intravaginal use for the prevention of sexually transmitted diseases is imperative. Previous studies have suggested that bile salts may inhibit human immunodeficiency virus infection; however, their activities against other sexually transmitted pathogens have not been reported. To further explore the potential role of bile salts in preventing sexually transmitted diseases, we examined the in vitro activities and cytotoxicities of select bile salts againstChlamydia trachomatis, herpes simplex virus (types 1 and 2),Neisseria gonorrhoeae, and human immunodeficiency virus in comparison to those of nonoxynol-9 and benzalkonium chloride using both primary cells and cell lines derived from the human female genital tract. We found that taurolithocholic acid 3-sulfate and a combination of glycocholic acid and taurolithocholic acid 3-sulfate showed excellent activity against all of the pathogens assayed. Moreover, taurolithocholic acid 3-sulfate alone or in combination was less cytotoxic than nonoxynol-9 and benzalkonium chloride. Thus, taurolithocholic acid 3-sulfate alone or in combination warrants further evaluation as a candidate topical microbicidal agent.
Efficacy of Doxycycline, Azithromycin, or Trovafloxacin for Treatment of Experimental Rocky Mountain Spotted Fever in Dogs
Authors: Breitschwerdt E. B. , Papich M. G. , Hegarty B. C. , Gilger B. , Hancock S. I. , Davidson M. G. 
Published: October 2018

ABSTRACTDogs were experimentally inoculated withRickettsia rickettsii(canine origin) in order to compare the efficacies of azithromycin and trovafloxacin to that of the current antibiotic standard, doxycycline, for the treatment of Rocky Mountain spotted fever. Clinicopathologic parameters, isolation of rickettsiae in tissue culture, and PCR amplification of rickettsial DNA were used to evaluate the response to therapy or duration of illness (untreated infection control group) in the four groups. Concentrations of the three antibiotics in plasma and blood cells were measured by high-performance liquid chromatography. Doxycycline and trovafloxacin treatments resulted in more-rapid defervescence, whereas all three antibiotics caused rapid improvement in attitudinal scores, blood platelet numbers, and the albumin/total-protein ratio. Based upon detection of retinal vascular lesions by fluorescein angiography, trovafloxacin and doxycycline substantially decreased rickettsia-induced vascular injury to the eye, whereas the number of ocular lesions in the azithromycin group did not differ from that in the infection control group. As assessed by tissue culture isolation, doxycycline resulted in the earliest apparent clearance of viable circulating rickettsiae; however, rickettsial DNA could still be detected in the blood of some dogs from all four groups on day 21 postinfection, despite our inability to isolate viable rickettsiae at that point. As administered in this study, trovafloxacin was as efficacious as doxycycline but azithromycin proved less efficacious, possibly due to the short duration of administration.
LY303366 Exhibits Rapid and Potent Fungicidal Activity in Flow Cytometric Assays of Yeast Viability
Authors: Green Lisa J. , Marder Philip , Mann Larry L. , Chio Li-Chun , Current William L. 
Published: October 2018

ABSTRACT

LY303366 is a semisynthetic analog of the antifungal lipopeptide echinocandin B that inhibits (1,3)-β-
d
-glucan synthase and exhibits efficacy in animal models of human fungal infections. In this study, we utilized flow cytometric analysis of propidium iodide uptake, single-cell sorting, and standard microbiological plating methods to study the antifungal effect of LY303366 on
Saccharomyces cerevisiae
and
Candida albicans
. Our data indicate that an initial 5-min pulse treatment with LY303366 caused yeasts to take up propidium iodide and lose their ability to grow. Amphotericin B and cilofungin required longer exposure periods (30 and 180 min, respectively) and higher concentrations to elicit these fungicidal effects. These two measurements of fungicidal activity by LY303366 were highly correlated (
r
> 0.99) in concentration response and time course experiments. As further validation, LY303366-treated yeasts that stained with propidium iodide were unable to grow in single-cell-sorted cultures. Our data indicate that LY303366 is potent and rapidly fungicidal for actively growing yeasts. The potency and rapid action of this new fungicidal compound suggest that LY303366 may be useful for antifungal therapy.
Clavulanate Induces Expression of the
Pseudomonas aeruginosa
AmpC Cephalosporinase at Physiologically Relevant Concentrations and Antagonizes the Antibacterial Activity of Ticarcillin
Authors: Lister Philip D. , Gardner Victoria M. , Sanders Christine C. 
Published: October 2018

ABSTRACT

Although previous studies have indicated that clavulanate may induce AmpC expression in isolates of
Pseudomonas aeruginosa
, the impact of this inducer activity on the antibacterial activity of ticarcillin at clinically relevant concentrations has not been investigated. Therefore, a study was designed to determine if the inducer activity of clavulanate was associated with in vitro antagonism of ticarcillin at pharmacokinetically relevant concentrations. By the disk approximation methodology, clavulanate induction of AmpC expression was observed with 8 of 10 clinical isolates of
P. aeruginosa
. Quantitative studies demonstrated a significant induction of AmpC when clavulanate-inducible strains were exposed to the peak concentrations of clavulanate achieved in human serum with the 3.2- and 3.1-g doses of ticarcillin-clavulanate. In studies with three clavulanate-inducible strains in an in vitro pharmacodynamic model, antagonism of the bactericidal effect of ticarcillin was observed in some tests with regimens simulating a 3.1-g dose of ticarcillin-clavulanate and in all tests with regimens simulating a 3.2-g dose of ticarcillin-clavulanate. No antagonism was observed in studies with two clavulanate-noninducible strains. In contrast to clavulanate, tazobactam failed to induce AmpC expression in any strains, and the pharmacodynamics of piperacillin-tazobactam were somewhat enhanced over those of piperacillin alone against all strains studied. Overall, the data collected from the pharmacodynamic model suggested that induction per se was not always associated with reduced killing but that a certain minimal level of induction by clavulanate was required before antagonism of the antibacterial activity of its companion drug occurred. Nevertheless, since clinically relevant concentrations of clavulanate can antagonize the bactericidal activity of ticarcillin, the combination of ticarcillin-clavulanate should be avoided when selecting an antipseudomonal β-lactam for the treatment of
P. aeruginosa
infections, particularly in immunocompromised patients. For piperacillin-tazobactam, induction is not an issue in the context of treating this pathogen.
Fourteen-Member Macrolides Inhibit Interleukin-8 Release by Human Eosinophils from Atopic Donors
Authors: Kohyama Tadashi , Takizawa Hajime , Kawasaki Shin , Akiyama Norihisa , Sato Makoto , Ito Koji 
Published: October 2018

ABSTRACTMacrolide antibiotics such as erythromycin have been reported to be effective for asthma. However, the precise mechanisms of this effect remain unclear. We studied the effect of erythromycin, clarithromycin, josamycin, and other antibiotics on the release by eosinophils of interleukin-8 (IL-8), a potent chemokine for inflammatory cells, including eosinophils themselves. Human eosinophils were isolated from atopic patients, and the effects of the drugs on IL-8 release were evaluated. Only 14-member macrolides (erythromycin and clarithromycin) showed a concentration-dependent suppressive effect on IL-8 release (control, 100%; erythromycin at 1 μg/ml, 67.82% ± 3.45% [P< 0.01]; clarithromycin at 5 μg/ml, 56.81% ± 9.61% [P< 0.01]). The effect was found at therapeutic concentrations and appeared to occur at the posttranscriprtional level. In contrast, a 16-member macrolide (josamycin) had no significant effect. We suggest that 14-member macrolides inhibit IL-8 release by eosinophils and may thereby prevent the autocrine cycle necessary for the recruitment of these cells into the airways.
Integron-Mediated Rifampin Resistance in
Pseudomonas aeruginosa
Authors: Tribuddharat Chanwit , Fennewald Michael 
Published: October 2018

ABSTRACT

A new rifampin resistance gene,
arr-2
, has been found in
Pseudomonas aeruginosa
. The ARR-2 protein shows 54% amino acid identity to the rifampin ADP-ribosylating transferase encoded by the
arr
gene from
Mycobacterium smegmatis
. This
arr-2
gene is located on a gene cassette within a class I integron.
Pharmacokinetics of Oral Zidovudine Entrapped in Biodegradable Nanospheres in Rabbits
Authors: Callender Diana P. , Jayaprakash Nalini , Bell Aaron , Petraitis Vidmantas , Petratienes Ruta , Candelario Myrna , Schaufele Robert , Dunn James M. , Sei Shizuko , Walsh Thomas J. , Balis Frank M. 
Published: October 2018

ABSTRACT
The pharmacokinetic profile of oral zidovudine entrapped in a 50:50 polyactide-coglycolide matrix (nanospheres) was compared to those of standard oral and parenteral zidovudine formulations in rabbits. The bioavailability of zidovudine nanospheres at 50 mg/kg of body weight was 76%, and this dose achieved prolonged exposure to zidovudine compared to standard formulations without an increase in the drug’s peak concentration.
Assessment of the Effect of Amphotericin B on the Vitality of
Candida albicans
Authors: Liao Robert S. , Rennie Robert P. , Talbot James A. 
Published: October 2018

ABSTRACT

The processes involved in cell death are complex, and individual techniques measure specific fractions of the total population. The interaction of
Candida albicans
with amphotericin B was measured with fluorescent probes with different cellular affinities. These were used to provide qualitative and quantitative information of physiological parameters which contribute to fungal cell viability. SYBR Green I and 5,(6)-carboxyfluorescein were used to assess membrane integrity, and bis-(1,3-dibutylbarbituric acid)trimethine oxonol and 3,3-dihexyloxacarbocyanine iodide were used to evaluate alterations in membrane potential. The fluorescent indicators were compared with replication competency, the conventional indicator of viability. By using these tools, the evaluation of the response of
C. albicans
to amphotericin B time-kill curves delineated four categories which may represent a continuum between alive and dead. The data showed that replication competency (CFU per milliliter) as determined by conventional antifungal susceptibility techniques provided only an estimate of inhibition. Interpretation of fluorescent staining characteristics indicated that
C. albicans
cells which were replication incompetent after exposure to greater than 0.5 μg of amphotericin B per ml still maintained degrees of physiological function.
Negative Regulation of the
Pseudomonas aeruginosa
Outer Membrane Porin OprD Selective for Imipenem and Basic Amino Acids
Authors: Ochs Martina M. , McCusker Matthew P. , Bains Manjeet , Hancock Robert E. W. 
Published: October 2018

ABSTRACT

Pseudomonas aeruginosa
OprD is a specific porin which facilitates the uptake of basic amino acids and imipenem, a carbapenem antibiotic. Resistance to imipenem due to the loss of OprD is an important mechanism for the loss of clinical effectiveness. To investigate the negative regulatory mechanisms influencing
oprD
expression, a gene upstream of the coregulated
mexEF-oprN
efflux operon, designated
mexT
, was cloned. The predicted 304-amino-acid mature MexT protein showed strong homology to LysR-type regulators. When overexpressed it induced the expression of the
mexEF-oprN
efflux operon while decreasing the level of expression of OprD. The use of an
oprD
::
xylE
transcriptional fusion indicated that it acted by repressing the transcription of
oprD
. Salicylate, a weak aromatic acid known to reduce porin expression and induce low levels of multiple antibiotic resistance in
Escherichia coli
, was able to induce imipenem resistance and reduce the expression of OprD but not multiple antibiotic resistance or OprN expression in
P. aeruginosa
. This was also demonstrated to occur at the level of transcription. Acetyl salicylate and benzoate, but not catechol, were also able to reduce the levels of OprD in the
P. aeruginosa
outer membranes. These OprD-suppressing compounds increased imipenem resistance even in a
mexT
-overexpressing and
nfxC
mutant backgrounds, suggesting that such resistance is independent of the MexT repressor and that
oprD
is influenced by more than a single mechanism of repression.
Streptococcus pneumoniae
DNA Gyrase and Topoisomerase IV: Overexpression, Purification, and Differential Inhibition by Fluoroquinolones
Authors: Pan Xiao-Su , Fisher L. Mark 
Published: October 2018

ABSTRACT

Streptococcus pneumoniae gyrA
and
gyrB
genes specifying the DNA gyrase subunits have been cloned into pET plasmid vectors under the control of an inducible T7 promoter and have been separately expressed in
Escherichia coli
. Soluble 97-kDa GyrA and 72-kDa GyrB proteins bearing polyhistidine tags at their respective C-terminal and N-terminal ends were purified to apparent homogeneity by one-step nickel chelate column chromatography and were free of host
E. coli
topoisomerase activity. Equimolar amounts of the gyrase subunits reconstituted ATP-dependent DNA supercoiling with comparable activity to gyrase of
E. coli
and
Staphylococcus aureus
. In parallel,
S. pneumoniae
topoisomerase IV ParC and ParE subunits were similarly expressed in
E. coli
, purified to near homogeneity as 93- and 73-kDa proteins, and shown to generate efficient ATP-dependent DNA relaxation and DNA decatenation activities. Using the purified enzymes, we examined the inhibitory effects of three paradigm fluoroquinolones—ciprofloxacin, sparfloxacin, and clinafloxacin—which previous genetic studies with
S. pneumoniae
suggested act preferentially through topoisomerase IV, through gyrase, and through both enzymes, respectively. Surprisingly, all three quinolones were more active in inhibiting purified topoisomerase IV than gyrase, with clinafloxacin showing the greatest inhibitory potency. Moreover, the tested agents were at least 25-fold more effective in stabilizing a cleavable complex (the relevant cytotoxic lesion) with topoisomerase IV than with gyrase, with clinafloxacin some 10- to 32-fold more potent against either enzyme, in line with its superior activity against
S. pneumoniae
. The uniform target preference of the three fluoroquinolones for topoisomerase IV in vitro is in apparent contrast to the genetic data. We interpret these results in terms of a model for bacterial killing by quinolones in which cellular factors can modulate the effects of target affinity to determine the cytotoxic pathway.
Intravenous Penciclovir for Treatment of Herpes Simplex Infections in Immunocompromised Patients: Results of a Multicenter, Acyclovir-Controlled Trial
Authors: Lazarus Hillard M. , Belanger Robert , Candoni Anna , Aoun Mickaël , Jurewicz Regina , Marks Lynn ,   The Penciclovir Immunocompromised Study Group
Published: October 2018

ABSTRACTThe efficacy and safety of penciclovir (PCV) for the treatment of herpes simplex virus (HSV) infections in immunocompromised (IC) patients were studied in a double-blind, acyclovir (ACV)-controlled, multicenter study. A total of 342 patients with mucocutaneous HSV infections received 5 mg of PCV per kg every 12 or 8 h (q12h or q8h) or 5 mg of ACV per kg q8h, beginning within 72 h of lesion onset and continuing for up to 7 days. The mean age of the patients was 49 years; 94% were white and 52% were female. The main reasons for their IC states were hematologic disorder (63%) and transplant plus hematologic disorder (16%). Clinical and virological assessments were performed daily during the 7-day treatment and then every other day until lesion healing. The primary efficacy parameter addressed new lesion formation. Secondary end points focused on viral shedding, healing, and pain. Approximately 20% of patients in each treatment group developed new lesions during therapy; thus, equivalence with ACV (defined prospectively) was demonstrated for both q12h and q8h PCV regimens. For all three treatment groups, the median time to the cessation of viral shedding was 4 days and the median time to complete healing was 8 days; there were no statistically significant differences in the rates of complete healing or the cessation of viral shedding when the results for PCV q12h and q8h were compared with those for ACV q8h. In addition, there was no statistically significant difference between PCV q12h or q8h, compared with ACV q8h, for the resolution of pain. PCV was well tolerated, with an adverse event profile comparable to that of ACV. In conclusion, PCV q12h is a well-tolerated and effective therapy for mucocutaneous HSV infection in IC patients and offers a reduced frequency of dosing compared with ACV q8h.
Ultrasonic Enhancement of Antibiotic Action on
Escherichia coli
Biofilms: an In Vivo Model
Authors: Rediske Andrea M. , Roeder Beverly L. , Brown Maren K. , Nelson Jared L. , Robison Rachel L. , Draper David O. , Schaalje G. Bruce , Robison Richard A. , Pitt William G. 
Published: October 2018

ABSTRACT

Biofilm infections are a common complication of prosthetic devices in humans. Previous in vitro research has determined that low-frequency ultrasound combined with aminoglycoside antibiotics is an effective method of killing biofilms. We report the development of an in vivo model to determine if ultrasound enhances antibiotic action. Two 24-h-old
Escherichia coli
(ATCC 10798) biofilms grown on polyethylene disks were implanted subcutaneously on the backs of New Zealand White female rabbits, one on each side of the spine. Low-frequency (28.48-kHz) and low-power-density (100- and 300-mW/cm
2
) continuous ultrasound treatment was applied for 24 h with and without systemic administration of gentamicin. The disks were then removed, and the number of viable bacteria on each disk was determined. At the low ultrasonic power used in this study, exposure to ultrasound only (no gentamicin) caused no significant difference in bacterial viability. In the presence of antibiotic, there was a significant reduction due to 300-mW/cm
2
ultrasound (
P
= 0.0485) but no significant reduction due to 100-mW/cm
2
ultrasound. Tissue damage to the skin was noted at the 300-mW/cm
2
treatment level. Further development of this technique has promise in treatment of clinical implant infections.
N-Acylated and
d
Enantiomer Derivatives of a Nonamer Core Peptide of Lactoferricin B Showing Improved Antimicrobial Activity
Authors: Wakabayashi Hiroyuki , Matsumoto Hiroshi , Hashimoto Koichi , Teraguchi Susumu , Takase Mitsunori , Hayasawa Hirotoshi 
Published: October 2018

ABSTRACT

N-acylated or
d
enantiomer peptide derivatives based on the sequence RRWQWRMKK in lactoferricin B demonstrated antimicrobial activities greater than those of lactoferricin B against bacteria and fungi. The most potent peptide, conjugated with an 11-carbon-chain acyl group, showed two to eight times lower MIC than lactoferricin B.
Metronidazole Therapy in Mice Infected with Tuberculosis
Authors: Brooks Jason V. , Furney Synthia K. , Orme Ian M. 
Published: October 2018

ABSTRACTThe capacity of metronidazole to inhibit the growth ofMycobacterium tuberculosiswas tested in in vitro and in vivo mouse models. In vitro addition of metronidazole to cultures of infected bone marrow-derived macrophages had no effect, nor did it increase the reduction in bacterial load due to isoniazid. In vivo, metronidazole did not reduce bacterial numbers in the lungs of aerosol-infected mice during the active stage of the disease, during a phase of containment, or after prolonged isoniazid therapy (Cornell model). A small but significant reduction was seen if metronidazole therapy was given during an established chronic disease state 100 days after aerosol administration. These data indicate that under most conditionsM. tuberculosisorganisms are not in a metabolic state in which they are susceptible to the action of metronidazole and, hence, that this drug would be of limited clinical value.
Resistance to β-Lactam Antibiotics in
Pseudomonas aeruginosa
Due to Interplay between the MexAB-OprM Efflux Pump and β-Lactamase
Authors: Nakae Taiji , Nakajima Akira , Ono Toshihisa , Saito Kohjiro , Yoneyama Hiroshi 
Published: October 2018

ABSTRACT

We evaluated the roles of the MexAB-OprM efflux pump and β-lactamase in β-lactam resistance in
Pseudomonas aeruginosa
by constructing OprM-deficient, OprM basal level, and OprM fully expressed mutants from β-lactamase-negative, -inducible, and -overexpressed strains. We conclude that, with the notable exception of imipenem, the MexAB-OprM pump contributes significantly to β-lactam resistance in both β-lactamase-negative and β-lactamase-inducible strains, while the contribution of the MexAB-OprM efflux system is negligible in strains with overexpressed β-lactamase. Overexpression of the efflux pump alone contributes to the high level of β-lactam resistance in the absence of β-lactamase.