bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased Mortality with Accessory Gene Regulator (
agr
) Dysfunction in
Staphylococcus aureus
among Bacteremic Patients
Authors: Schweizer Marin L. , Furuno Jon P. , Sakoulas George , Johnson J. Kristie , Harris Anthony D. , Shardell Michelle D. , McGregor Jessina C. , Thom Kerri A. , Perencevich Eli N. 
Published: December 2010

ABSTRACT

Accessory gene regulator (
agr
) dysfunction in
Staphylococcus aureus
has been associated with a longer duration of bacteremia. We aimed to assess the independent association between
agr
dysfunction in
S. aureus
bacteremia and 30-day in-hospital mortality. This retrospective cohort study included all adult inpatients with
S. aureus
bacteremia admitted between 1 January 2003 and 30 June 2007. Severity of illness prior to culture collection was measured using the modified acute physiology score (APS).
agr
dysfunction in
S. aureus
was identified semiquantitatively by using a δ-hemolysin production assay. Cox proportional hazard models were used to measure the association between
agr
dysfunction and 30-day in-hospital mortality, statistically adjusting for patient and pathogen characteristics. Among 814 patient admissions complicated by
S. aureus
bacteremia, 181 (22%) patients were infected with
S. aureus
isolates with
agr
dysfunction. Overall, 18% of patients with
agr
dysfunction in
S. aureus
died, compared to 12% of those with functional
agr
in
S. aureus
(
P
= 0.03). There was a trend toward higher mortality among patients with
S. aureus
with
agr
dysfunction (adjusted hazard ratio [HR], 1.34; 95% confidence interval [CI], 0.87 to 2.06). Among patients with the highest APS (scores of >28),
agr
dysfunction in
S. aureus
was significantly associated with mortality (adjusted HR, 1.82; 95% CI, 1.03 to 3.21). This is the first study to demonstrate an independent association between
agr
dysfunction and mortality among severely ill patients. The δ-hemolysin assay examining
agr
function may be a simple and inexpensive approach to predicting patient outcomes and potentially optimizing antibiotic therapy.
Characterization of the Biosynthesis Gene Cluster for the Pyrrole Polyether Antibiotic Calcimycin (A23187) in
Streptomyces chartreusis
NRRL 3882
Authors: Wu Qiulin , Liang Jingdan , Lin Shuangjun , Zhou Xiufen , Bai Linquan , Deng Zixin , Wang Zhijun 
Published: December 2010

ABSTRACT

The pyrrole polyether antibiotic calcimycin (A23187) is a rare ionophore that is specific for divalent cations. It is widely used as a biochemical and pharmacological tool because of its multiple, unique biological effects. Here we report on the cloning, sequencing, and mutational analysis of the 64-kb biosynthetic gene cluster from
Streptomyces chartreusis
NRRL 3882. Gene replacements confirmed the identity of the gene cluster, and
in silico
analysis of the DNA sequence revealed 27 potential genes, including 3 genes for the biosynthesis of the α-ketopyrrole moiety, 5 genes that encode modular type I polyketide synthases for the biosynthesis of the spiroketal ring, 4 genes for the biosynthesis of 3-hydroxyanthranilic acid, an
N
-methyltransferase tailoring gene, a resistance gene, a type II thioesterase gene, 3 regulatory genes, 4 genes with other functions, and 5 genes of unknown function. We propose a pathway for the biosynthesis of calcimycin and assign the genes to the biosynthesis steps. Our findings set the stage for producing much desired calcimycin derivatives using genetic modification instead of chemical synthesis.
Miconazole Oral Gel Increases Exposure to Oral Oxycodone by Inhibition of CYP2D6 and CYP3A4
Authors: Grönlund Juha , Saari Teijo I. , Hagelberg Nora , Neuvonen Pertti J. , Olkkola Klaus T. , Laine Kari 
Published: December 2010

ABSTRACTOur aim was to assess the effect of miconazole oral gel on the pharmacokinetics of oral oxycodone. In an open crossover study with two phases, 12 healthy volunteers took a single oral dose of 10 mg of immediate-release oxycodone with or without thrice-daily 85-mg miconazole oral gel treatment. The plasma concentrations of oxycodone and its oxidative metabolites were measured for 48 h. Pharmacological effects of oxycodone were recorded for 12 h. Pharmacokinetic parameters were compared by use of the geometric mean ratios (GMRs) and their 90% confidence interval (CIs). Pretreatment with miconazole oral gel caused a strong inhibition of the CYP2D6-dependent metabolism and moderate inhibition of the CYP3A4-dependent metabolism of oxycodone. The mean area under the concentration-time curve (AUC) from time zero to infinity (AUC0-∞; GMR, 1.63; 90% CI, 1.48 to 1.79) and the peak concentration of oxycodone (GMR, 1.31; 90% CI, 1.19 to 1.44) were increased. The AUC of the CYP2D6-dependent metabolite oxymorphone was greatly decreased (GMR, 0.17; 90% CI, 0.09 to 0.31) by miconazole gel, whereas that of the CYP3A4-dependent metabolite noroxycodone was increased (GMR, 1.30; 90% CI, 1.15 to 1.47) by miconazole gel. Differences in the pharmacological response to oxycodone between phases were insignificant. Miconazole oral gel increases the exposure to oral oxycodone, but the clinical relevance of the interaction is moderate. Miconazole oral gel produces a rather strong inhibitory effect on CYP2D6, which deserves further study.
Comparative Efficacy and Safety of Moxifloxacin and Clindamycin in the Treatment of Odontogenic Abscesses and Inflammatory Infiltrates: a Phase II, Double-Blind, Randomized Trial
Authors: Cachovan Georg , Böger Rainer H. , Giersdorf Ina , Hallier Olaf , Streichert Thomas , Haddad Munif , Platzer Ursula , Schön Gerhard , Wegscheider Karl , Sobottka Ingo 
Published: December 2010

ABSTRACT

Moxifloxacin penetrates well into oromaxillary tissue and covers the causative pathogens that show an increasing resistance to standard antibiotics. Clinical reports suggest that moxifloxacin may be effective for the treatment of odontogenic infections that can lead to serious complications. The objective of this prospective, randomized, double-blind, multicenter study was to compare the efficacies and safeties of moxifloxacin and clindamycin for the medical treatment of patients with gingival inflammatory infiltrates and as an adjuvant therapy for patients with odontogenic abscesses requiring surgical treatment. Patients received either 400 mg moxifloxacin
per os
once daily or 300 mg clindamycin
per os
four times daily for 5 days consecutively. The primary efficacy endpoint was the percent reduction in patients' perceived pain on a visual analogue scale at days 2 to 3 from baseline. Primary analysis included 21 moxifloxacin- and 19 clindamycin-treated patients with infiltrates and 15 moxifloxacin- and 16 clindamycin-treated patients with abscesses. The mean pain reductions were 61.0% (standard deviation [SD], 46.9%) with moxifloxacin versus 23.4% (SD, 32.1%) with clindamycin (
P
= 0.006) for patients with infiltrates and 55.8% (SD, 24.8%) with moxifloxacin versus 42.7% (SD, 48.5%) with clindamycin (
P
= 0.358) for patients with abscesses. A global efficacy assessment at days 2 to 3 and 5 to 7 showed faster clinical responses with moxifloxacin in both abscess and infiltrate patients. Rates of adverse events were lower in moxifloxacin- than in clindamycin-treated patients. In patients with inflammatory infiltrates, moxifloxacin was significantly more effective in reducing pain at days 2 to 3 of therapy than clindamycin. No significant differences between groups were found for patients with odontogenic abscesses.
Systematic Review and Meta-Analysis of the Effectiveness and Safety of Tigecycline for Treatment of Infectious Disease
Authors: Cai Yun , Wang Rui , Liang Beibei , Bai Nan , Liu Youning 
Published: December 2010

ABSTRACT

The aim of this study was to compare the efficacy and safety of tigecycline, a newly developed glycylcycline antibiotic, with those of empirical antibiotic regimens which have been reported to possess good efficacy for complicated skin and skin structure infections (cSSSIs), complicated intra-abdominal infections (cIAIs), community-acquired pneumonia (CAP), and other infections caused by methicillin-resistant
Staphylococcus aureus
(MRSA) or vancomycin-resistant
Enterococcus
(VRE). A meta-analysis of randomized controlled trials (RCTs) identified in PubMed, the Cochrane Library, and Embase was performed. Eight RCTs involving 4,651 patients were included in the meta-analysis. Compared with therapy with empirical antibiotic regimens, tigecycline monotherapy was associated with similar clinical treatment success rates (for the clinically evaluable [CE] population, odds ratio [OR] = 0.92, 95% confidence interval [CI] = 0.76 to 1.12,
P
= 0.42; for the clinical modified intent-to-treat [c-mITT] population, OR = 0.86, 95% CI = 0.74 to 1.01,
P
= 0.06) and similar microbiological treatment success rates (for the microbiologically evaluable [ME] population, OR = 0.86, 95% CI = 0.69 to 1.07,
P
= 0.19). The incidence of adverse events in the tigecycline group was significantly higher than that in the other therapy groups with a statistical margin (for the modified intent-to-treat [mITT] population, OR = 1.33, 95% CI = 1.17 to 1.52,
P
< 0.0001), especially in the digestive system (mITT population, OR = 2.41, 95% CI = 1.67 to 3.46,
P
< 0.00001). No difference regarding all-cause mortality and drug-related mortality between tigecycline and the other regimens was found, although numerically higher mortality was found in the tigecycline group. This meta-analysis provides evidence that tigecycline monotherapy may be used as effectively as the comparison therapy for cSSSI, cIAIs, CAP, and infections caused by MRSA/VRE. However, because of the high risk of mortality, AEs, and emergence of resistant isolates, prudence with the clinical use of tigecycline monotherapy in infections is required.
Oxidative Stress Induction of the MexXY Multidrug Efflux Genes and Promotion of Aminoglycoside Resistance Development in
Pseudomonas aeruginosa
Authors: Fraud Sebastien , Poole Keith 
Published: December 2010

ABSTRACT

Exposure to reactive oxygen species (ROS) (e.g., peroxide) was shown to induce expression of the PA5471 gene, which was previously shown to be required for antimicrobial induction of the MexXY components of the MexXY-OprM multidrug efflux system and aminoglycoside resistance determinant in
Pseudomonas aeruginosa. mexXY
was also induced by peroxide exposure, and this too was PA5471 dependent. The prospect of ROS promoting
mexXY
expression and aminoglycoside resistance recalls
P. aeruginosa
infection of the chronically inflamed lungs of cystic fibrosis (CF) patients, where the organism is exposed to ROS and where MexXY-OprM predominates as the mechanism of aminoglycoside resistance. While ROS did not enhance aminoglycoside resistance
in vitro
, long-term (8-day) exposure of
P. aeruginosa
to peroxide (mimicking chronic
in vivo
ROS exposure) increased aminoglycoside resistance frequency, dependent upon PA5471 and
mexXY
. This enhanced resistance frequency was also seen in a mutant strain overexpressing PA5471, in the absence of peroxide, suggesting that induction of PA5471 by peroxide was key to peroxide enhancement of aminoglycoside resistance frequency. Resistant mutants selected following peroxide exposure were typically pan-aminoglycoside-resistant, with
mexXY
generally required for this resistance. Moreover, PA5471 was required for
mexXY
expression and aminoglycoside resistance in these as well as several CF isolates examined.
Enhancement of Experimental Cutaneous Leishmaniasis byLeishmaniaMolecules Is Dependent on Interleukin-4, Serine Protease/Esterase Activity, and Parasite and Host Genetic Backgrounds
Authors: Silva Virgínia M. G. , Larangeira Daniela F. , Oliveira Pablo R. S. , Sampaio Romina B. , Suzart Paula , Nihei Jorge S. , Teixeira Márcia C. A. , Mengel José O. , dos-Santos Washington L. C. , Pontes-de-Carvalho Lain 
Published: December 2010

ABSTRACTMost inbred strains of mice, like the BALB/c strain, are susceptible toLeishmania amazonensisinfections and resistant toLeishmania braziliensisinfections. This parasite-related difference could result from the activity of anL. amazonensis-specific virulence factor. In agreement with this hypothesis, it is shown here that the intravenous injection of BALB/c mice withL. amazonensisamastigote extract (LaE) but not theL. braziliensisextract confers susceptibility toL. braziliensisinfection. This effect was associated with high circulating levels of IgG1 anti-L. amazonensisantibodies and with an increase in interleukin-4 (IL-4) production and a decrease in gamma interferon production by draining lymph node cells. Moreover, the effect was absent in IL-4-knockout mice. The biological activity in theLaE was not mediated by amphiphilic molecules and was inhibited by pretreatment of the extract with irreversible serine protease inhibitors. These findings indicate that theLaE contains a virulence-related factor that (i) enhances theLeishmaniainfection by promoting Th2-type immune responses, (ii) is not one of the immunomodulatoryLeishmaniamolecules described so far, and (iii) is either a serine protease or has an effect that depends on that protease activity. In addition to beingLeishmaniaspecies specific, the infection-enhancing activity was also shown to depend on the host genetic makeup, asLaE injections did not affect the susceptibility of C57BL/6 mice toL. braziliensisinfection. The identification ofLeishmaniamolecules with infection-enhancing activity could be important for the development of a vaccine, since the up- or downmodulation of the immune response against a virulence factor could well contribute to controlling the infection.
Inactivation of
bb0184
, Which Encodes Carbon Storage Regulator A, Represses the Infectivity of
Borrelia burgdorferi
Authors: Sze Ching Wooen , Li Chunhao 
Published: December 2010

ABSTRACT

The genome of
Borrelia burgdorferi
, the Lyme disease spirochete, encodes a homolog (the
bb0184
gene product) of the carbon storage regulator A protein (CsrA
Bb
); recent studies reported that CsrA
Bb
is involved in the regulation of several infectivity factors of
B. burgdorferi
. However, the mechanism involved remains unknown. In this report, a

csrA
Bb

mutant was constructed and complemented in an infectious B31A3 strain. Subsequent animal studies showed that the mutant failed to establish an infection in mice, highlighting that CsrA
Bb
is required for the infectivity of
B. burgdorferi
. Western blot analyses revealed that the virulence-associated factors OspC, DbpB, and DbpA were attenuated in the

csrA
Bb

mutant. The Rrp2-RpoN-RpoS pathway (σ
54
-σ
S
sigma factor cascade) is a central regulon that governs the expression of
ospC
,
dbpB
, and
dbpA
. Further analyses found that the level of RpoS was significantly decreased in the mutant, while the level of Rrp2 remained unchanged. A recent study reported that the overexpression of BB0589, a phosphate acetyl-transferase (Pta) that converts acetyl-phosphate to acetyl-coenzyme A (CoA), led to the inhibition of RpoS and OspC expression, suggesting that acetyl-phosphate is an activator of Rrp2. Along with this report, we found that CsrA
Bb
binds to the leader sequence of the
bb0589
transcript and that the intracellular level of acetyl-CoA in the

csrA
Bb

mutant was significantly increased compared to that of the wild type, suggesting that more acetyl-phosphate was being converted to acetyl-CoA in the mutant. Collectively, these results suggest that CsrA
Bb
may influence the infectivity of
B. burgdorferi
via regulation of acetate metabolism and subsequent activation of the Rrp2-RpoN-RpoS pathway.
Use of aDictyosteliumModel for Isolation of Genetic Loci Associated with Phagocytosis and Virulence inKlebsiella pneumoniae
Authors: Pan Yi-Jiun , Lin Tzu-Lung , Hsu Chun-Ru , Wang Jin-Town 
Published: December 2010

ABSTRACTPhagocytosis resistance is an important virulence factor inKlebsiella pneumoniae.Dictyosteliumhas been used to study the interaction between phagocytes and bacteria because of its similarity to mammalian macrophages. In this study, we used aDictyosteliummodel to investigate genes for resistance to phagocytosis in NTUH-K2044, a strain ofK. pneumoniaecausing pyogenic liver abscess that is highly resistant to phagocytosis. A total of 2,500 transposon mutants were screened by plaque assay, and 29 of them permitted phagocytosis byDictyostelium. In the 29 mutants, six loci were identified; three were capsular synthesis genes. Of the other three, one was related to carnitine metabolism, one encoded a subunit of protease (clpX), and one encoded a lipopolysaccharide O-antigen transporter (wzm). Deletion and complementation of these genes showed that only ΔclpXand Δwzmmutants became susceptible toDictyosteliumphagocytosis, and their complementation restored the phagocytosis resistance phenotype. These two mutants were also susceptible to phagocytosis by human neutrophils and revealed attenuated virulence in a mouse model, implying that they play important roles in the pathogenesis ofK. pneumoniae. Furthermore, we demonstrated thatclpP, which exists in an operon withclpX, was also involved in resistance to phagocytosis. The transcriptional profile of ΔclpXwas examined by microarray analysis and revealed a 3-fold lower level of expression of capsular synthesis genes. Therefore, we have identified genes involved in resistance to phagocytosis inK. pneumoniaeusingDictyostelium, and this model is useful to explore genes associated with resistance to phagocytosis in heavily encapsulated bacteria.
ygs
Is a Novel Gene That Influences Biofilm Formation and the General Stress Response of
Staphylococcus epidermidis
Authors: Wang Xing , Niu Chen , Sun Gang , Dong Dandan , Villaruz Amer E. , Li Min , Wang Decheng , Wang Jianping , Otto Michael , Gao Qian 
Published: December 2010

ABSTRACT

Infections caused by the nosocomial pathogen
Staphylococcus epidermidis
frequently develop on implanted medical devices and involve biofilm formation. Biofilms are surface-attached microbial communities that show increased resistance to drug treatment and mechanisms of innate host defense. In this study, a mutant library of the clinical isolate
S. epidermidis
1457 was constructed using mariner-based transposon mutagenesis. About a thousand mutants were screened, and 12 mutants were identified as significantly defective in biofilm formation. We focused on a mutant in which the transposon had inserted in a gene with unknown function,
SERP0541
, which is annotated as a gene encoding a GSP13-like general stress response protein. The gene was named
ygs
(encoding an unknown

g

eneral

s

tress protein). Various stresses, including heat, pH, high osmolarity, and ethanol affected the survival of the
ygs
mutant to a significantly higher degree than the wild-type strain and led to increased expression of
ygs
. Furthermore, synthesis of polysaccharide intercellular adhesin (PIA) and transcription of the PIA biosynthetic operon were significantly decreased in the
ygs
mutant. These results are in accordance with the putative involvement of
ygs
in stress-response gene regulation and indicate that
ygs
influences biofilm development by controlling PIA-dependent biofilm accumulation. Moreover,
ygs
had a significant impact on the formation of biofilms and metastatic disease in two catheter-related rat infection models. Our study shows that the
ygs
gene controls
S. epidermidis
biofilm accumulation and stress resistance, representing a key regulator of both structural and physiological biofilm characteristics with a significant impact on biofilm-associated infection.
AnIn VivoHigh-Throughput Screening Approach Targeting the Type IV Secretion System Component VirB8 Identified Inhibitors ofBrucella abortus2308 Proliferation
Authors: Paschos Athanasios , den Hartigh Andreas , Smith Mark A. , Atluri Vidya L. , Sivanesan Durga , Tsolis Renée M. , Baron Christian 
Published: December 2010

ABSTRACTAs bacterial pathogens develop resistance against most currently used antibiotics, novel alternatives for treatment of microbial infectious diseases are urgently needed. Targeting bacterial virulence functions in order to disarm pathogens represents a promising alternative to classical antibiotic therapy. Type IV secretion systems, which are multiprotein complexes in the cell envelope that translocate effectors into host cells, are critical bacterial virulence factors in many pathogens and excellent targets for such “antivirulence” drugs. The VirB8 protein from the mammalian pathogenBrucellawas chosen as a specific target, since it is an essential type IV secretion system component, it participates in multiple protein-protein interactions, and it is essential for the assembly of this translocation machinery. The bacterial two-hybrid system was adapted to assay VirB8 interactions, and a high-throughput screen identified specific small-molecule inhibitors. VirB8 interaction inhibitors also reduced the levels of VirB8 and of other VirB proteins, and many of them inhibitedvirBgene transcription inBrucella abortus2308, suggesting that targeting of the secretion system has complex regulatory effectsin vivo. One compound strongly inhibited the intracellular proliferation ofB. abortus2308 in a J774 macrophage infection model. The results presented here show thatin vivoscreens with the bacterial two-hybrid assay are suited to the identification of inhibitors ofBrucellatype IV secretion system function.
Development of a Secondary Immune Response toMycobacterium tuberculosisIs Independent of Toll-Like Receptor 2
Authors: McBride Amanda , Bhatt Kamlesh , Salgame Padmini 
Published: December 2010

ABSTRACTPublished work indicates that the contribution of Toll-like receptor 2 (TLR2) to host resistance during acuteMycobacterium tuberculosisinfection is marginal. However, in these studies, TLR2 participation in the memory immune response toM. tuberculosiswas not determined. The substantialin vitroevidence thatM. tuberculosisstrongly triggers TLR2 on dendritic cells and macrophages to bring about either activation or inhibition of antigen-presenting cell (APC) functions, along with accumulating evidence that memory T cell development can be calibrated by TLR signals, led us to question the role of TLR2 in host resistance to secondary challenge withM. tuberculosis. To address this question, a memory immunity model was employed, and the response of TLR2-deficient (TLR2 knockout [TLR2KO]) mice following a secondary exposure toM. tuberculosiswas compared to that of wild-type (WT) mice based on assessment of the bacterial burden, recall response, phenotype of recruited T cells, and granulomatous response. We found that upon rechallenge withM. tuberculosis, both WT and TLR2KO immune mice displayed similarly enhanced resistance to infection in comparison to their naïve counterparts. The frequencies ofM. tuberculosis-specific gamma interferon (IFN-γ)-producing T cells, the phenotypes of recruited T cells, and the granulomatous responses were also similar between WT and TLR2KO immune mice. Together, the findings from this study indicate that TLR2 signaling does not influence memory immunity toM. tuberculosis.