bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of Ceftaroline Fosamil against Penicillin-Sensitive and -Resistant Streptococcus pneumoniae in an Experimental Rabbit Meningitis Model
Authors: Cottagnoud P. , Cottagnoud M. , Acosta F. , Stucki A. 
Published: July 2013

ABSTRACT

Ceftaroline is a new cephalosporin with bactericidal activity against resistant Gram-positive organisms, including methicillin-resistant
Staphylococcus aureus
(MRSA) and penicillin-resistant
Streptococcus pneumoniae
, as well as common Gram-negative organisms. This study tested the prodrug, ceftaroline fosamil, against a penicillin-sensitive and a penicillin-resistant strain of
S. pneumoniae
in an experimental rabbit meningitis model. The penetration of ceftaroline into inflamed meninges was approximately 14%. Ceftaroline fosamil was slightly superior to ceftriaxone against the penicillin-sensitive strain and significantly superior to the combination of ceftriaxone and vancomycin against the penicillin-resistant strain.
Antimicrobial Activity of the Pleuromutilin Antibiotic BC-3781 against Bacterial Pathogens Isolated in the SENTRY Antimicrobial Surveillance Program in 2010
Authors: Paukner Susanne , Sader Helio S. , Ivezic-Schoenfeld Zrinka , Jones Ronald N. 
Published: July 2013

ABSTRACT

BC-3781 is a novel semisynthetic pleuromutilin antibiotic inhibiting bacterial protein synthesis. BC-3781 has completed a phase 2 clinical trial in acute bacterial skin and skin structure infections (ABSSSI). Its antibacterial spectrum additionally covers the predominant pathogens causing community-acquired bacterial pneumonia (CABP). In this study, the antibacterial activity of BC-3781 was evaluated against a contemporary collection of 10,035 bacterial isolates predominately causing ABSSSI and CABP, among other infections, collected within the SENTRY Antimicrobial Surveillance Program worldwide in 2010. BC-3781 exhibited potent activity against organisms commonly isolated from ABSSSI such as
Staphylococcus aureus
(MIC
50/90
, 0.12/0.12 μg/ml; 99.8% inhibited at ≤0.5 μg/ml), beta-hemolytic streptococci (MIC
50/90
, 0.03/0.03 μg/ml; 99.3% inhibited at ≤0.5 μg/ml), and coagulase-negative staphylococci (CoNS; MIC
50/90
, 0.06/0.12 μg/ml; 97.8% inhibited at ≤1 μg/ml). BC-3781 displayed similar MIC distributions among methicillin-susceptible (MSSA) and methicillin-resistant (MRSA)
S. aureus
strains. BC-3781 was also active against
Enterococcus faecium
, with 76.3% of vancomycin-susceptible and 97.0% of vancomycin-resistant isolates being inhibited at BC-3781 concentrations of ≤1 μg/ml. Beta-hemolytic and viridans group streptococci were highly susceptible to BC-3781, with 99.3% and 96.7% of isolates inhibited at ≤0.5 μg/ml, respectively. Further, activity of BC-3781 against
Streptococcus pneumoniae
(MIC
50/90
, 0.12/0.25 μg/ml),
Haemophilus influenzae
(MIC
50/90
, 1/2 μg/ml), and
Moraxella catarrhalis
(MIC
50/90
, 0.12/0.25 μg/ml) was not negatively influenced by β-lactamase production or resistance to other antimicrobial classes tested. In all, BC-3781 displayed a very potent antibacterial profile including the most prevalent bacterial pathogens causing ABSSSI and CABP, thus warranting further clinical development of this antibiotic in these and possibly other indications.
The Perfidious Effect of Topical Placebo: Calibration of Staphylococcus aureus Ventilator-Associated Pneumonia Incidence within Selective Digestive Decontamination Studies versus the Broader Evidence Base
Authors: Hurley James C. 
Published: July 2013

ABSTRACT

Among various methods for preventing ventilator-associated pneumonia (VAP), the evidence base for selective digestive decontamination (SDD) appears most compelling. However, the extent of
Staphylococcus aureus
emergence with SDD use remains uncertain. Groups from 37 observational studies and component (control and intervention) groups from 58 studies of SDD and other methods of VAP prevention were sourced exclusively from 10 systematic reviews.
S. aureus
as a proportion of VAP isolates (
S. aureus
isolate proportion [
S. aureus
IP]) among component groups was calibrated versus that among observational groups (the benchmark). The influence of topical placebo used for blinding purposes and other group-level factors was estimated using generalized estimating equation methods (GEE). The mean
S. aureus
IP is 22% (95% confidence interval [CI], 19 to 25) for 37 observational groups versus 32% (24 to 41) and 20% (15 to 25) for 22 control groups from the SDD evidence base which did versus did not receive topical placebo, respectively. In GEE models including all 148 observational and component groups, membership of a control (
P
= 0.03) or intervention (
P
< 0.001) group of an SDD study that used topical placebo was associated with higher
S. aureus
IP, whereas, in contrast, membership of these groups was without effect on
Pseudomonas aeruginosa
. Topical placebo is implicated as a vehicle for selective cross-infection with
S. aureus
within the specific context of the SDD evidence base. This effect of topical placebo is perfidious; it could contribute to the higher VAP incidence and inflate the apparent “effectiveness” of SDD. The SDD evidence base requires reappraisal.
Impact of Fluoroquinolone Resistance on Bactericidal and Sterilizing Activity of a Moxifloxacin-Containing Regimen in Murine Tuberculosis
Authors: Fillion Aurélie , Aubry Alexandra , Brossier Florence , Chauffour Aurélie , Jarlier Vincent , Veziris Nicolas 
Published: July 2013

ABSTRACT

It has been shown previously that fluoroquinolone resistance (defined by resistance to at least 2 mg/liter ofloxacin) has a different impact on moxifloxacin monotherapy depending on the mutation in the sole fluoroquinolone target in
Mycobacterium tuberculosis
, i.e., DNA gyrase. Since tuberculosis treatment relies on multidrug therapy, we wished to determine the impact of fluoroquinolone resistance on the bactericidal and sterilizing activity of a second-line antituberculous regimen containing moxifloxacin. A total of 280 mice were inoculated with the wild-type
Mycobacterium tuberculosis
H37Rv strain or one of 3 isogenic fluoroquinolone-resistant mutant strains with increasing moxifloxacin resistance (the GyrB D500N, GyrA A90V, and GyrA D94G strains) and then treated for 6 months with a second-line regimen containing moxifloxacin, pyrazinamide, and ethionamide supplemented with amikacin during the first 2 months. Mice were sacrificed during treatment for measurement of bactericidal activity and 3 months after treatment completion for measurement of relapse rates (sterilizing activity). The CFU counts decreased faster in mice inoculated with the wild type than in mice inoculated with the mutant strains. The relapse rate after treatment completion was different among mice inoculated with mutant strains in relation to the drug resistance level: wild type, 0%; GyrB D500N strain, 33%; GyrA A90V strain, 50%; and GyrA D94G strain, 86%. The relapse rate observed with the GyrB D500N strain was the only one not statistically different from that observed with the wild-type strain. We demonstrated that the impact on sterilizing activity of the most active second-line drug regimen containing moxifloxacin depends on the MIC of moxifloxacin. We suggest that the precise level of moxifloxacin resistance be determined for all strains resistant to 2 mg/liter ofloxacin.
Correlations of Antibiotic Use and Carbapenem Resistance in Enterobacteriaceae
Authors: McLaughlin Milena , Advincula M. Renee , Malczynski Michael , Qi Chao , Bolon Maureen , Scheetz Marc H. 
Published: July 2013

ABSTRACT

Epidemiological studies have shown a link between carbapenem use and resistance; however, the clinical relationship between antibiotic consumption and the epidemiology of carbapenem-intermediate or -resistant
Enterobacteriaceae
(CIRE) remains unclear. This study sought to analyze temporal antibiotic consumption trends for relationships with incident CIRE. In total, 310,892 days of therapy and 55 deduplicated CIRE were analyzed. When conservative corrections were applied for multiple comparisons, carbapenem class use and piperacillin-tazobactam use retained significant positive and negative relationships with the incidence of CIRE, respectively.
Membrane Perturbation Action Mode and Structure-Activity Relationships of Protonectin, a Novel Antimicrobial Peptide from the Venom of the Neotropical Social Wasp Agelaia pallipes pallipes
Authors: Wang Kairong , Dang Wen , Yan Jiexi , Chen Ru , Liu Xin , Yan Wenjin , Zhang Bangzhi , Xie Junqiu , Zhang Jindao , Wang Rui 
Published: July 2013

ABSTRACT

With the extensive use of antibiotics, multidrug-resistant bacteria emerge frequently. New antimicrobial agents with novel modes of action are urgently needed. It is now widely accepted that antimicrobial peptides (AMPs) could be promising alternatives to conventional antibiotics. In this study, we aimed to study the antimicrobial activity and mechanism of action of protonectin, a cationic peptide from the venom of the neotropical social wasp
Agelaia pallipes pallipes
. We demonstrated that protonectin exhibits potent antimicrobial activity against a spectrum of bacteria, including multidrug-resistant strains. To further understand this mechanism, the structural features of protonectin and its analogs were studied by circular dichroism (CD). The CD spectra demonstrated that protonectin and its natural analog polybia-CP formed a typical α-helical conformation in the membrane-mimicking environment, while its proline-substituted analog had much lower or even no α-helix conformation. Molecular dynamics simulations indicated that the α-helical conformation in the membrane is required for the exhibition of antibacterial activity. In conclusion, protonectin exhibits potent antimicrobial activity by disruption of the integrity of the bacterial membrane, and its α-helical confirmation in the membrane is essential for this action.
Biochemical Characterization of IMP-30, a Metallo-β-Lactamase with Enhanced Activity toward Ceftazidime
Authors: Pegg Kevin M. , Liu Eleanor M. , LaCuran Alecander E. , Oelschlaeger Peter 
Published: July 2013

ABSTRACT

IMP-type enzymes constitute a clinically important family of metallo-β-lactamases that has grown dramatically in the past decade to its current 45 known members. Here, we report the biochemical characterization of IMP-30 in comparison to IMP-1, from which it deviates by a single E59K mutation. Kinetics, MIC assays, docking, and molecular dynamics simulations support a scenario in which Lys59 interacts with the ceftazidime R
1
group, resulting in increased water access and enhanced turnover and MIC of ceftazidime.
Plasmodium Dipeptidyl Aminopeptidases as Malaria Transmission-Blocking Drug Targets
Authors: Tanaka Takeshi Q , Deu Edgar , Molina-Cruz Alvaro , Ashburne Michael J. , Ali Omar , Suri Amreena , Kortagere Sandhya , Bogyo Matthew , Williamson Kim C. 
Published: July 2013

ABSTRACT

The
Plasmodium falciparum
and
P. berghei
genomes each contain three dipeptidyl aminopeptidase (
dpap
) homologs.
dpap1
and -3 are critical for asexual growth, but the role of
dpap2
, the gametocyte-specific homolog, has not been tested. If DPAPs are essential for transmission as well as asexual growth, then a DPAP inhibitor could be used for treatment and to block transmission. To directly analyze the role of DPAP2, a
dpap2
-minus
P. berghei
(
Pbdpap2
Δ) line was generated. The
Pbdpap2
Δ parasites grew normally, differentiated into gametocytes, and generated sporozoites that were infectious to mice when fed to a mosquito. However,
Pbdpap1
transcription was >2-fold upregulated in the
Pbdpap2
Δ clonal lines, possibly compensating for the loss of
Pbdpap2
. The role of DPAP1 and -3 in the
dpap2
Δ parasites was then evaluated using a DPAP inhibitor, ML4118S. When ML4118S was added to the
Pbdpap2
Δ parasites just before a mosquito membrane feed, mosquito infectivity was not affected. To assess longer exposures to ML4118S and further evaluate the role of DPAPs during gametocyte development in a parasite that causes human malaria, the
dpap2
deletion was repeated in
P. falciparum
. Viable
P. falciparum dpap2
(
Pfdpap2
)-minus parasites were obtained that produced morphologically normal gametocytes. Both wild-type and
Pfdpap2
-negative parasites were sensitive to ML4118S, indicating that, unlike many antimalarials, ML4118S has activity against parasites at both the asexual and sexual stages and that DPAP1 and -3 may be targets for a dual-stage drug that can treat patients and block malaria transmission.
T4-Like Phage Bp7, a Potential Antimicrobial Agent for Controlling Drug-Resistant Escherichia coli in Chickens
Authors: Zhang Can , Li Wenli , Liu Wenhua , Zou Ling , Yan Chen , Lu Kai , Ren Huiying 
Published: July 2013

ABSTRACTChicken-pathogenicEscherichia coliis severely endangering the poultry industry in China and worldwide, and antibiotic therapy is facing an increasing problem of antibiotic resistance. Bacteriophages can kill bacteria with no known activity in human or animal cells, making them an attractive alternative to antibiotics. In this study, we present the characteristics of a novel virulent bacteriophage, Bp7, specifically infecting pathogenic multidrug-resistantE. coli. Phage Bp7 was isolated from chicken feces. Bp7 belongs to the familyMyoviridae, possessing an elongated icosahedral head and contractile sheathed tail. It has a 168-kb double-stranded DNA genome. For larger yields, its optimal multiplicity of infection (MOI) to infectE. coliwas about 0.001. The latent period was 10 to 15 min, and the burst size was 90 PFU/infected cell. It was stable both at pH 5.0 to 10.0 and at 40°C or 50°C for at least 1 h. Bp7 could infect 46% of pathogenic clinicalE. colistrains. Bp7 harbored 791 open reading frames (ORFs) and 263 possible genes. Among the 263 genes, 199 possessed amino acid sequence identities with ORFs of phage T4, 62 had identities with other T4-like phages, and only one lacked any database match. The genome of Bp7 manifested obvious division and rearrangement compared to phages T4, JS98, and IME08. Bp7 is a new member of the “T4-like” genus, familyMyoviridae. Its wide host range, strong cell-killing activity, and high stability to pH make it an alternative to antimicrobials for controlling drug-resistantE. coliin chickens.
prfA
-Like Transcription Factor Gene
lmo0753
Contributes to
l
-Rhamnose Utilization in Listeria monocytogenes Strains Associated with Human Food-Borne Infections
Authors: Salazar Joelle K. , Wu Zhuchun , McMullen P. David , Luo Qin , Freitag Nancy E. , Tortorello Mary Lou , Hu Shencai , Zhang Wei 
Published: July 2013

ABSTRACT

Listeria monocytogenes
is a food-borne bacterial pathogen and the causative agent of human and animal listeriosis. Among the three major genetic lineages of
L. monocytogenes
(i.e., LI, LII, and LIII), LI and LII are predominantly associated with food-borne listeriosis outbreaks, whereas LIII is rarely implicated in human infections. In a previous study, we identified a Crp/Fnr family transcription factor gene,
lmo0753
, that was highly specific to outbreak-associated LI and LII but absent from LIII. Lmo0753 shares two conserved functional domains, including a DNA binding domain, with the well-characterized master virulence regulator PrfA in
L. monocytogenes
. In this study, we constructed
lmo0753
deletion and complementation mutants in two fully sequenced
L. monocytogenes
LII strains, 10403S and EGDe, and compared the flagellar motility, phospholipase C production, hemolysis, and intracellular growth of the mutants and their respective wild types. Our results suggested that
lmo0753
plays a role in hemolytic activity in both EGDe and 10403S. More interestingly, we found that deletion of
lmo0753
led to the loss of
l
-rhamnose utilization in EGDe, but not in 10403S. RNA-seq analysis of EGDe Δ
0753
incubated in phenol red medium containing
l
-rhamnose as the sole carbon source revealed that 126 (4.5%) and 546 (19.5%) out of 2,798 genes in the EGDe genome were up- and downregulated more than 2-fold, respectively, compared to the wild-type strain. Genes related to biotin biosynthesis, general stress response, and rhamnose metabolism were shown to be differentially regulated. Findings from this study collectively suggested varied functional roles of
lmo0753
in different LII
L. monocytogenes
strain backgrounds associated with human listeriosis outbreaks.
Bacillus subtilis Strain Engineered for Treatment of Soil-Transmitted Helminth Diseases
Authors: Hu Yan , Miller Melanie M. , Derman Alan I. , Ellis Brian L. , Monnerat Rose Gomes , Pogliano Joe , Aroian Raffi V. 
Published: July 2013

ABSTRACT

Soil-transmitted helminths (hookworms, whipworms, and large roundworms) are agents of intestinal roundworm diseases of poverty that infect upwards of 2 billion people worldwide. A great challenge in treating these diseases is the development of anthelmintic therapeutics that are inexpensive, can be produced in great quantity, and are capable of delivery under varied and adverse environmental conditions. A potential solution to this challenge is the use of live bacteria that are acceptable for human consumption, e.g.,
Bacillus subtilis
, and that can be engineered with therapeutic properties. In this study, we expressed the
Bacillus thuringiensis
anthelmintic protein Cry5B in a bacterial strain that has been used as a model for live bacterial therapy,
Bacillus subtilis
PY79. PY79 transformed with a Cry5B expression plasmid (PY79-Cry5B) is able to express Cry5B from the endogenous
B. thuringiensis cry5B
promoter. During sporulation of PY79-Cry5B, Cry5B is packaged as a crystal. Furthermore, Cry5B produced in PY79 is bioactive, with a 50% lethal concentration (LC
50
) of 4.3 μg/ml against the roundworm
Caenorhabditis elegans
. PY79-Cry5B was a significantly effective therapeutic in experimental
Ancylostoma ceylanicum
hookworm infections of hamsters. A single 10-mg/kg (0.071 μmol/kg of body weight) dose of Cry5B administered as a Cry5B-PY79 spore crystal lysate achieved a 93% reduction in hookworm burdens, which is superior on a molar level to reductions seen with clinically used anthelmintics. Given that a bacterial strain such as this one can be produced cheaply in massive quantities, our results demonstrate that the engineering and delivery of live bacterial strains have great potential to treat a significant contributor to poverty worldwide, namely, hookworm disease and other soil-transmitted helminthiasis.
Conserved Regions of Gonococcal TbpB Are Critical for Surface Exposure and Transferrin Iron Utilization
Authors: Ostberg Karen L. , DeRocco Amanda J. , Mistry Shreni D. , Dickinson Mary Kathryne , Cornelissen Cynthia Nau 
Published: July 2013

ABSTRACT

The transferrin-binding proteins TbpA and TbpB enable
Neisseria gonorrhoeae
to obtain iron from human transferrin. The lipoprotein TbpB facilitates, but is not strictly required for, TbpA-mediated iron acquisition. The goal of the current study was to determine the contribution of two conserved regions within TbpB to the function of this protein. Using site-directed mutagenesis, the first mutation we constructed replaced the lipobox (LSAC) of TbpB with a signal I peptidase cleavage site (LAAA), while the second mutation deleted a conserved stretch of glycine residues immediately downstream of the lipobox. We then evaluated the resulting mutants for effects on TbpB expression, surface exposure, and transferrin iron utilization. Western blot analysis and palmitate labeling indicated that the lipobox, but not the glycine-rich motif, is required for lipidation of TbpB and tethering to the outer membrane. TbpB was released into the supernatant by the mutant that produces TbpB LSAC. Neither mutation disrupted the transport of TbpB across the bacterial cell envelope. When these mutant TbpB proteins were produced in a strain expressing a form of TbpA that requires TbpB for iron acquisition, growth on transferrin was either abrogated or dramatically diminished. We conclude that surface tethering of TbpB is required for optimal performance of the transferrin iron acquisition system, while the presence of the polyglycine stretch near the amino terminus of TbpB contributes significantly to transferrin iron transport function. Overall, these results provide important insights into the functional roles of two conserved motifs of TbpB, enhancing our understanding of this critical iron uptake system.
Modeling Klebsiella pneumoniae Pathogenesis by Infection of the Wax Moth Galleria mellonella
Authors: Insua José Luis , Llobet Enrique , Moranta David , Pérez-Gutiérrez Camino , Tomás Anna , Garmendia Junkal , Bengoechea José A. 
Published: July 2013

ABSTRACTThe implementation of infection models that approximate human disease is essential for understanding pathogenesis at the molecular level and for testing new therapies before they are entered into clinical stages. Insects are increasingly being used as surrogate hosts because they share, with mammals, essential aspects of the innate immune response to infections. We examined whether the larva of the wax mothGalleria mellonellacould be used as a host model to conceptually approximateKlebsiella pneumoniae-triggered pneumonia. We report that theG. mellonellamodel is capable of distinguishing between pathogenic and nonpathogenicKlebsiellastrains. Moreover,K. pneumoniaeinfection ofG. mellonellamodels some of the known features ofKlebsiella-induced pneumonia, i.e., cell death associated with bacterial replication, avoidance of phagocytosis by phagocytes, and the attenuation of host defense responses, chiefly the production of antimicrobial factors. Similar to the case for the mouse pneumonia model, activation of innate responses improvedG. mellonellasurvival against subsequentKlebsiellachallenge. Virulence factors necessary in the mouse pneumonia model were also implicated in theGalleriamodel. We found that mutants lacking capsule polysaccharide, lipid A decorations, or the outer membrane proteins OmpA and OmpK36 were attenuated inGalleria. All mutants activatedG. mellonelladefensive responses. TheGalleriamodel also allowed us to monitorKlebsiellagene expression. The expression levels ofcpsand the loci implicated in lipid A remodeling peaked during the first hours postinfection, in a PhoPQ- and PmrAB-governed process. Taken together, these results support the utility ofG. mellonellaas a surrogate host for assessing infections withK. pneumoniae.
H-NS Is a Negative Regulator of the Two Hemolysin/Cytotoxin Gene Clusters in Vibrio anguillarum
Authors: Mou Xiangyu , Spinard Edward J. , Driscoll Maureen V. , Zhao Wenjing , Nelson David R. 
Published: July 2013

ABSTRACT

Hemolysins produced by
Vibrio anguillarum
have been implicated in the development of hemorrhagic septicemia during vibriosis, a fatal fish disease. Previously, two hemolysin gene clusters responsible for the hemolysis and cytotoxicity of
V. anguillarum
were identified: the
vah1-plp
gene cluster and the
rtxACHBDE
gene cluster. In this study, we identified the
hns
gene, which encodes the H-NS protein and acts as a negative regulator of both gene clusters. The
V. anguillarum
H-NS protein shares strong homology with other bacterial H-NS proteins. An
hns
mutant exhibited increased hemolytic activity and cytotoxicity compared to the wild-type strain. Complementation of the
hns
mutation restored hemolytic activity and cytotoxicity levels to nearly wild-type levels. Furthermore, expression of
rtxA
,
rtxH
,
rtxB
,
vah1
, and
plp
increased in the
hns
mutant and decreased in the
hns
-complemented mutant strain compared to expression in the wild-type strain. Additionally, experiments using DNase I showed that purified recombinant H-NS protected multiple sites in the promoter regions of both gene clusters. The
hns
mutant also exhibited significantly attenuated virulence against rainbow trout. Complementation of the
hns
mutation restored virulence to wild-type levels, suggesting that H-NS regulates many genes that affect fitness and virulence. Previously, we showed that HlyU is a positive regulator of expression for both gene clusters. In this study, we demonstrate that upregulation by
hlyU
is
hns
dependent, suggesting that H-NS acts to repress or silence both gene clusters and HlyU acts to relieve that repression or silencing.