bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of Fluoroquinolones and Macrolides on Eradication and Resistance of Haemophilus influenzae in Chronic Obstructive Pulmonary Disease
Authors: Pettigrew Melinda M. , Tsuji Brian T. , Gent Janneane F. , Kong Yong , Holden Patricia N. , Sethi Sanjay , Murphy Timothy F. 
Published: May 2016

ABSTRACT

Little is known about the effect of antibiotics on eradication of carriage and development of resistance in
Haemophilus influenzae
in individuals with chronic obstructive pulmonary disease (COPD). Our goals were to assess antibiotic susceptibilities, prevalence of resistance genes, and development of resistance in
H. influenzae
and to evaluate the effect of macrolide and fluoroquinolone administration on
H. influenzae
eradication. Data were from a 15-year longitudinal study of COPD. Genome sequence data were used to determine genotype and identify resistance genes. MICs of antibiotics were determined by reference broth microdilution. Generalized linear mixed models were used to evaluate associations between antibiotic use and
H. influenzae
eradication. We examined 267
H. influenzae
isolates from 77 individuals. All newly acquired
H. influenzae
isolates were susceptible to azithromycin. Five of 27 (19%) strains developed 4-fold increases in azithromycin MICs and reached or exceeded the susceptibility breakpoint (≤4 μg/ml) during exposure.
H. influenzae
isolates were uniformly susceptible to ciprofloxacin, levofloxacin, and moxifloxacin (MIC
90
s of 0.015, 0.015, and 0.06, respectively); there were no mutations in quinolone resistance-determining regions. Fluoroquinolone administration was associated with increased
H. influenzae
eradication compared to macrolides (odds ratio [OR], 16.67; 95% confidence interval [CI], 2.67 to 104.09). There was no difference in
H. influenzae
eradication when comparing macrolide administration to no antibiotic (OR, 1.89; 95% CI, 0.43 to 8.30). Fluoroquinolones are effective in eradicating
H. influenzae
in individuals with COPD. Macrolides are ineffective in eradicating
H. influenzae
, and their use in COPD patients may lead to decreased macrolide susceptibility and resistance.
Sideromimic Modification of Lactivicin Dramatically Increases Potency against Extensively Drug-Resistant Stenotrophomonas maltophilia Clinical Isolates
Authors: Calvopiña Karina , Umland Klaus-Daniel , Rydzik Anna M. , Hinchliffe Philip , Brem Jürgen , Spencer James , Schofield Christopher J. , Avison Matthew B. 
Published: May 2016

ABSTRACT

Acetamido derivatives of the naturally antibacterial non-β-lactam lactivicin (LTV) have improved activity against their penicillin binding protein targets and reduced hydrolysis by β-lactamases, but penetration into Gram-negative bacteria is still relatively poor. Here we report that modification of the LTV lactone with a catechol-type siderophore increases potency 1,000-fold against
Stenotrophomonas maltophilia
, a species renowned for its insusceptibility to antimicrobials. The MIC
90
of modified lactone compound 17 (LTV17) against a global collection of extensively drug-resistant clinical
S. maltophilia
isolates was 0.063 μg · ml
−1
. Sideromimic modification does not reduce the ability of LTVs to induce production of the L1 and L2 β-lactamases in
S. maltophilia
and does not reduce the rate at which LTVs are hydrolyzed by L1 or L2. We conclude, therefore, that lactivicin modification with a siderophore known to be preferentially used by
S. maltophilia
substantially increases penetration via siderophore uptake. LTV17 has the potential to be developed as a novel antimicrobial for treatment of infections by
S. maltophilia
. More generally, our work shows that sideromimic modification in a species-targeted manner might prove useful for the development of narrow-spectrum antimicrobials that have reduced collateral effects.
Potency and Stereoselectivity of Cyclopropavir Triphosphate Action on Human Cytomegalovirus DNA Polymerase
Authors: Chen Han , Li Chengwei , Zemlicka Jiri , Gentry Brian G. , Bowlin Terry L. , Coen Donald M. 
Published: May 2016

ABSTRACT

Cyclopropavir (CPV) is a promising antiviral drug against human cytomegalovirus (HCMV). As with ganciclovir (GCV), the current standard for HCMV treatment, activation of CPV requires multiple steps of phosphorylation and is enantioselective. We hypothesized that the resulting CPV triphosphate (CPV-TP) would stereoselectively target HCMV DNA polymerase and terminate DNA synthesis. To test this hypothesis, we synthesized both enantiomers of CPV-TP [(+) and (−)] and investigated their action on HCMV polymerase. Both enantiomers inhibited HCMV polymerase competitively with dGTP, with (+)-CPV-TP exhibiting a more than 20-fold lower apparent

K
i

than (−)-CPV-TP. Moreover, (+)-CPV-TP was a more potent inhibitor than GCV-TP. (+)-CPV-TP also exhibited substantially lower apparent

K
m

and somewhat higher apparent
k
cat
values than (−)-CPV-TP and GCV-TP for incorporation into DNA by the viral polymerase. As is the case for GCV-TP, both CPV-TP enantiomers behaved as nonobligate chain terminators, with the polymerase terminating DNA synthesis after incorporation of one additional nucleotide. These results elucidate how CPV-TP acts on HCMV DNA polymerase and help explain why CPV is more potent against HCMV replication than GCV.
Ecological Effect of Solithromycin on Normal Human Oropharyngeal and Intestinal Microbiota
Authors: Rashid Mamun-Ur , Rosenborg Staffan , Panagiotidis Georgios , Holm Johan , Söderberg Löfdal Karin , Weintraub Andrej , Nord Carl Erik 
Published: May 2016

ABSTRACT

Solithromycin is a new fluoroketolide. The purpose of the present study was to investigate the effect of orally administered solithromycin on the human oropharyngeal and intestinal microbiota. Thirteen healthy volunteers (median age, 27.3 years) received oral solithromycin at 800 mg on day 1 followed by 400 mg daily on days 2 to 7. Fecal and saliva samples were collected at baseline and on days 2, 5, 7, 9, 14, and 21 for pharmacokinetic and microbiological analyses. Plasma samples were collected predose on days 2, 5, and 7 as proof of exposure, and solithromycin concentration ranges were 21.9 to 258 ng/ml, 18.0 to 386 ng/ml, and 16.9 to 417 ng/ml, respectively. The solithromycin concentrations in feces were 15.8 to 65.4 mg/kg, 24.5 to 82.7 mg/kg, 21.4 to 82.7 mg/kg, 12.1 to 72.4 mg/kg, 0.2 to 25.6 mg/kg, and 0 to 0.5 mg/kg on days 2, 5, 7, 9, 14, and 21, respectively. The numbers of enterobacteria and enterococci decreased and were normalized on day 14. The numbers of lactobacilli and bifidobacteria decreased from day 2 to day 14 and were normalized on day 21. The clostridia decreased on days 2, 7, and 14 and were normalized on day 21. No
Clostridium difficile
strains or toxins were detected during the study period. The number of
Bacteroides
strains was not significantly changed. The solithromycin concentrations in saliva were 0 to 1.2 mg/liter, 0 to 0.5 mg/liter, 0 to 0.5 mg/liter, and 0 to 0.1 mg/liter on days 2, 5, 7, and 9, respectively. The numbers of streptococci decreased on day 2 and were normalized on day 5. The numbers of lactobacilli, prevotellae, fusobacteria, and leptotrichiae decreased from day 2 and were normalized on day 21.
Component Analysis of Multipurpose Contact Lens Solutions To Enhance Activity against Pseudomonas aeruginosa and Staphylococcus aureus
Authors: Lin Leo , Kim Janie , Chen Hope , Kowalski Regis , Nizet Victor 
Published: May 2016

ABSTRACT

More than 125 million people wear contact lenses worldwide, and contact lens use is the single greatest risk factor for developing microbial keratitis. We tested the antibacterial activity of multipurpose contact lens solutions and their individual component preservatives against the two most common pathogens causing bacterial keratitis,
Pseudomonas aeruginosa
and
Staphylococcus aureus
. The
in vitro
antibacterial activity of five multipurpose contact lens solutions (Opti-Free GP, Boston Simplus, Boston Advance, Menicare GP, and Lobob) was assayed by the standard broth dilution method. Synergy between the preservative components found in the top performing solutions was assayed using checkerboard and time-kill assays. The ISO 14729 criteria and the standard broth dilution method were used to define an optimized contact lens solution formulation against a clinical panel of drug-susceptible and drug-resistant
P. aeruginosa
and
S. aureus
strains. Preservatives with the biguanide function group, chlorhexidine and polyaminopropylbiguanide (PAPB), had the best antistaphylococcal activity, while EDTA was the best antipseudomonal preservative. The combination of chlorhexidine and EDTA had excellent synergy against
P. aeruginosa
. A solution formulation containing chlorhexidine (30 ppm), PAPB (5 ppm), and EDTA (5,000 ppm) had three to seven times more antipseudomonal activity than anything available to consumers today. A multipurpose contact lens solution containing a combination of chlorhexidine, PAPB, and EDTA could help to reduce the incidence of microbial keratitis for contact lens users worldwide.
Antimalarial Activity of Small-Molecule Benzothiazole Hydrazones
Authors: Sarkar Souvik , Siddiqui Asim A. , Saha Shubhra J. , De Rudranil , Mazumder Somnath , Banerjee Chinmoy , Iqbal Mohd S. , Nag Shiladitya , Adhikari Susanta , Bandyopadhyay Uday 
Published: May 2016

ABSTRACT

We synthesized a new series of conjugated hydrazones that were found to be active against malaria parasite
in vitro
, as well as
in vivo
in a murine model. These hydrazones concentration-dependently chelated free iron and offered antimalarial activity. Upon screening of the synthesized hydrazones, compound 5f was found to be the most active iron chelator, as well as antiplasmodial. Compound 5f also interacted with free heme (

K
D

[equilibrium dissociation constant] = 1.17 ± 0.8 μM), an iron-containing tetrapyrrole released after hemoglobin digestion by the parasite, and inhibited heme polymerization by parasite lysate. Structure-activity relationship studies indicated that a nitrogen- and sulfur-substituted five-membered aromatic ring present within the benzothiazole hydrazones might be responsible for their antimalarial activity. The dose-dependent antimalarial and heme polymerization inhibitory activities of the lead compound 5f were further validated by following [
3
H]hypoxanthine incorporation and hemozoin formation in parasite, respectively. It is worth mentioning that compound 5f exhibited antiplasmodial activity
in vitro
against a chloroquine/pyrimethamine-resistant strain of
Plasmodium falciparum
(K1). We also evaluated
in vivo
antimalarial activity of compound 5f in a murine model where a lethal multiple-drug-resistant strain of
Plasmodium yoelii
was used to infect Swiss albino mice. Compound 5f significantly suppressed the growth of parasite, and the infected mice experienced longer life spans upon treatment with this compound. During
in vitro
and
in vivo
toxicity assays, compound 5f showed minimal alteration in biochemical and hematological parameters compared to control. In conclusion, we identified a new class of hydrazone with therapeutic potential against malaria.
Quinolone Amides as Antitrypanosomal Lead Compounds with
In Vivo
Activity
Authors: Hiltensperger Georg , Hecht Nina , Kaiser Marcel , Rybak Jens-Christoph , Hoerst Alexander , Dannenbauer Nicole , Müller-Buschbaum Klaus , Bruhn Heike , Esch Harald , Lehmann Leane , Meinel Lorenz , Holzgrabe Ulrike 
Published: May 2016

ABSTRACT

Human African trypanosomiasis (HAT) is a major tropical disease for which few drugs for treatment are available, driving the need for novel active compounds. Recently, morpholino-substituted benzyl amides of the fluoroquinolone-type antibiotics were identified to be compounds highly active against
Trypanosoma brucei brucei
. Since the lead compound GHQ168 was challenged by poor water solubility in previous trials, the aim of this study was to introduce structural variations to GHQ168 as well as to formulate GHQ168 with the ultimate goal to increase its aqueous solubility while maintaining its
in vitro
antitrypanosomal activity. The pharmacokinetic parameters of spray-dried GHQ168 and the newly synthesized compounds GHQ242 and GHQ243 in mice were characterized by elimination half-lives ranging from 1.5 to 3.5 h after intraperitoneal administration (4 mice/compound), moderate to strong human serum albumin binding for GHQ168 (80%) and GHQ243 (45%), and very high human serum albumin binding (>99%) for GHQ242. For the lead compound, GHQ168, the apparent clearance was 112 ml/h and the apparent volume of distribution was 14 liters/kg of body weight (BW). Mice infected with
T. b. rhodesiense
(STIB900) were treated in a stringent study scheme (2 daily applications between days 3 and 6 postinfection). Exposure to spray-dried GHQ168 in contrast to the control treatment resulted in mean survival durations of 17 versus 9 days, respectively, a difference that was statistically significant. Results that were statistically insignificantly different were obtained between the control and the GHQ242 and GHQ243 treatments. Therefore, GHQ168 was further profiled in an early-treatment scheme (2 daily applications at days 1 to 4 postinfection), and the results were compared with those obtained with a control treatment. The result was statistically significant mean survival times exceeding 32 days (end of the observation period) versus 7 days for the GHQ168 and control treatments, respectively. Spray-dried GHQ168 demonstrated exciting antitrypanosomal efficacy.
Geographic Differences in the Contribution of
ubiA
Mutations to High-Level Ethambutol Resistance in Mycobacterium tuberculosis
Authors: Lingaraju Subramanya , Rigouts Leen , Gupta Aditi , Lee Jongseok , Umubyeyi Alaine Nyaruhirira , Davidow Amy L. , German Susan , Cho EunJin , Lee Ji-im , Cho Sang-Nae , Kim Cheon Tae , Alland David , Safi Hassan 
Published: May 2016

ABSTRACT

Ethambutol (EMB) resistance can evolve through a multistep process, and mutations in the
ubiA
(
Rv3806c
) gene appear to be responsible for high-level EMB resistance in
Mycobacterium tuberculosis
. We evaluated the prevalence of
ubiA
and
embB
(
Rv3795
) mutations in EMB-resistant strains originating from Africa and South Korea. No differences in
embB
mutation frequencies were observed between strains from both origins. However,
ubiA
mutations were present in 45.5% ± 6.5% of the African EMB-resistant isolates but in only 9.5% ± 1.5% of the South Korean EMB-resistant isolates. The
ubiA
mutations associated with EMB resistance were localized to regions encoding the transmembrane domains of the protein, whereas the
embB
mutations were localized to regions encoding the extramembrane domains. Larger studies are needed to investigate the causes of increased
ubiA
mutations as a pathway to high-level EMB resistance in African countries, such as extended EMB usage during tuberculosis treatment.
High Systemic Exposure of Pyrazinoic Acid Has Limited Antituberculosis Activity in Murine and Rabbit Models of Tuberculosis
Authors: Lanoix Jean-Philippe , Tasneen Rokeya , O'Brien Paul , Sarathy Jansy , Safi Hassan , Pinn Michael , Alland David , Dartois Véronique , Nuermberger Eric 
Published: May 2016

ABSTRACTPyrazinamide (PZA) is a prodrug requiring conversion to pyrazinoic acid (POA) by an amidase encoded bypncAforin vitroactivity. Mutation ofpncAis the most common cause of PZA resistance in clinical isolates. To determine whether the systemic delivery of POA or host-mediated conversion of PZA to POA could circumvent such resistance, we evaluated the efficacy of orally administered and host-derived POAin vivo. Dose-ranging plasma and intrapulmonary POA pharmacokinetics and the efficacy of oral POA or PZA treatment against PZA-susceptible tuberculosis were determined in BALB/c and C3HeB/FeJ mice. The activity of host-derived POA was assessed in rabbits infected with apncA-null mutant and treated with PZA. Median plasma POA values for the area under the concentration-time curve from 0 h to infinity (AUC0–∞) were 139 to 222 μg·h/ml and 178 to 287 μg·h/ml after doses of PZA and POA of 150 mg/kg of body weight, respectively, in mice. Epithelial lining fluid POA concentrations in infected mice were comparable after POA and PZA administration. In chronically infected BALB/c mice, PZA at 150 mg/kg reduced lung CFU counts by >2 log10after 4 weeks. POA was effective only at 450 mg/kg, which reduced lung CFU counts by ∼0.7 log10. POA had no demonstrable bactericidal activity in C3HeB/FeJ mice, nor did PZA administered to rabbits infected with a PZA-resistant mutant. Oral POA administration and host-mediated conversion of PZA to POA producing plasma POA exposures comparable to PZA administration was significantly less effective than PZA. These results suggest that the intrabacillary delivery of POA and that producing higher POA concentrations at the site of infection will be more effective strategies for maximizing POA efficacy.
Stability of Novel Siderophore Cephalosporin S-649266 against Clinically Relevant Carbapenemases
Authors: Ito-Horiyama Tsukasa , Ishii Yoshikazu , Ito Akinobu , Sato Takafumi , Nakamura Rio , Fukuhara Norio , Tsuji Masakatsu , Yamano Yoshinori , Yamaguchi Keizo , Tateda Kazuhiro 
Published: May 2016

ABSTRACT

To better understand the antibacterial activity of S-649266 against carbapenemase producers, its stability against clinically relevant carbapenemases was investigated. The catalytic efficiencies (
k
cat
/

K
m

) of IMP-1, VIM-2, and L1 for S-649266 were 0.0048, 0.0050, and 0.024 μM
−1
s
−1
, respectively, which were more than 260-fold lower than that for meropenem. Only slight hydrolysis of S-649266 against KPC-3 was observed. NDM-1 hydrolyzed meropenem 3-fold faster than S-649266 at 200 μM.
Pharmacodynamic Evaluation of the Potential Clinical Utility of Fosfomycin and Meropenem in Combination Therapy against KPC-2-Producing Klebsiella pneumoniae
Authors: Albiero James , Sy Sherwin K. B. , Mazucheli Josmar , Caparroz-Assef Silvana Martins , Costa Bruno Buranello , Alves Janio Leal Borges , Gales Ana Cristina , Tognim Maria Cristina Bronharo 
Published: May 2016

ABSTRACT

KPC-producing
Klebsiella pneumoniae
causes serious infections associated with high death rates worldwide. Combination therapy consisting of fosfomycin and a carbapenem is better than monotherapy to combat multidrug-resistant microorganisms, but no dosages for the combination have been defined. The MICs of meropenem and fosfomycin were evaluated against 18 clinical isolates of KPC-2-producing
K. pneumoniae
. The activities of combination antimicrobials were also determined by the checkerboard method. The MIC
50
and MIC
90
of each agent alone and in combination were challenged against short (1.5-h) or prolonged (3-h) infusion regimens of meropenem (1 g every 8 h [q8h], 1.5 g q6h, 2 g q8h) and fosfomycin (4 g q8h, 6 g q6h, 8 g q8h) by Monte Carlo simulation to evaluate the time above the MIC of the free drug concentration as a percentage of the dosing interval (
f
T>MIC). The monotherapy MIC
50
s and MIC
90
s were 32 and 256 mg/liter for meropenem and 64 and 512 mg/liter for fosfomycin, respectively. Antimicrobial combination increased bacterial susceptibility to 1/4 the MIC
50
s and to 1/8 to 1/16 the MIC
90
s of monotherapy. The antimicrobial combination demonstrated a synergistic effect for at least two-thirds of the isolates. In combination therapy, fosfomycin regimens of 6 g q6h and 8 g q8h as a 3-h infusion against the MIC
50
and MIC
90
had better chances of achieving ≥90% probability of target attainment (PTA) of 70%
f
T>MIC. Meropenem regimens of 1.5 g q6h and 2 g q8h in prolonged infusion can achieve close to 90% PTA of 40%
f
T>MIC for MIC
50
but not MIC
90
. The significant reduction in the MIC values and the achievement of appropriate PTA demonstrated that regimens containing fosfomycin with meropenem can be effective against KPC-2-producing
K. pneumoniae
.
Transcription Regulation in Archaea
Authors: Gehring Alexandra M. , Walker Julie E. , Santangelo Thomas J. 
Published: May 2016

ABSTRACTThe known diversity of metabolic strategies and physiological adaptations of archaeal species to extreme environments is extraordinary. Accurate and responsive mechanisms to ensure that gene expression patterns match the needs of the cell necessitate regulatory strategies that control the activities and output of the archaeal transcription apparatus.Archaeaare reliant on a single RNA polymerase for all transcription, and many of the known regulatory mechanisms employed for archaeal transcription mimic strategies also employed for eukaryotic and bacterial species. Novel mechanisms of transcription regulation have become apparent by increasingly sophisticatedin vivoandin vitroinvestigations of archaeal species. This review emphasizes recent progress in understanding archaeal transcription regulatory mechanisms and highlights insights gained from studies of the influence of archaeal chromatin on transcription.
The IntXO-PSL Recombination System Is a Key Component of the Second Maintenance System for Bacillus anthracis Plasmid pXO1
Authors: Pomerantsev Andrei P. , Rappole Catherine , Chang Zanetta , Chahoud Margaret , Leppla Stephen H. 
Published: May 2016

ABSTRACT

We previously identified three noncontiguous regions on
Bacillus anthracis
plasmid pXO1 that comprise a system for accurate plasmid partitioning and maintenance. However, deletion of these regions did not decrease retention of certain shortened pXO1 plasmids during vegetative growth. Using two genetic tools developed for DNA manipulation in
B. anthracis
(the Cre-
loxP
and Flp-FRT systems), we found two other noncontiguous pXO1 regions that together are sufficient for plasmid stability. This second pXO1 maintenance system includes the
tubZ
and
tubR
genes, characteristic of a type III partitioning system, and the IntXO recombinase gene (GBAA_RS29165), encoding a tyrosine recombinase, along with its adjacent 37-bp perfect stem-loop (PSL) target. Insertion of either the
tubZ
and
tubR
genes or the IntXO-PSL system into an unstable mini-pXO1 plasmid did not restore plasmid stability. The need for the two components of the second pXO1 maintenance system follows from the sequential roles of IntXO-PSL in generating monomeric circular daughter pXO1 molecules (thereby presumably preventing dimer catastrophe) and of TubZ/TubR in partitioning the monomers during cell division. We show that the IntXO recombinase deletes DNA regions located between two PSL sites in a manner similar to the actions of the Cre-
loxP
and Flp-FRT systems.

IMPORTANCE
Tyrosine recombinases catalyze cutting and joining reactions between short specific DNA sequences. Three types of reactions occur: integration and excision of DNA segments, inversion of DNA segments, and separation of monomeric forms from replicating circular DNA molecules. Here we show that the newly discovered site-specific IntXO-PSL recombinase system that contributes to the maintenance of the
B. anthracis
plasmid pXO1 can be used for genome engineering in a manner similar to that of the Cre-
loxP
or Flp-FRT system.