bluuebunny/crossref_metadata_2025_split huggingface dataset:
OXA-163, an OXA-48-Related Class D β-Lactamase with Extended Activity Toward Expanded-Spectrum Cephalosporins
Authors: Poirel Laurent , Castanheira Mariana , Carrër Amélie , Rodriguez Carla Parada , Jones Ronald N. , Smayevsky Jorgelina , Nordmann Patrice 
Published: March 2011

ABSTRACT

Two
bla
OXA-48
-like-positive isolates (
Klebsiella pneumoniae
and
Enterobacter cloacae
) were recovered in Argentina in 2008 as part of a large-scale survey focused on multidrug resistance in
Enterobacteriaceae
. In both cases, sequencing identified β-lactamase OXA-163, differing from OXA-48 by a single amino substitution and a 4-amino-acid deletion. OXA-163 hydrolyzed penicillins, ceftazidime, and cefotaxime, whereas OXA-48 did not. However, OXA-163 had a much lower ability to hydrolyze carbapenems than OXA-48, therefore barely being considered a carbapenemase. In both isolates, the
bla
OXA-163
gene was located on plasmids that differed in structure and size. However, a detailed genetic analysis revealed a similar genetic context in those isolates, with the
bla
OXA-163
gene being bracketed by novel transposase genes, making this genetic environment different from that reported for the
bla
OXA-48
gene. This study identified the first class D β-lactamase compromising both extended-spectrum cephalosporin and carbapenem activities.
Quorum Sensing Inhibitors Increase the Susceptibility of Bacterial Biofilms to Antibiotics In Vitro and In Vivo
Authors: Brackman Gilles , Cos Paul , Maes Louis , Nelis Hans J. , Coenye Tom 
Published: March 2011

ABSTRACTAlthough the exact role of quorum sensing (QS) in various stages of biofilm formation, maturation, and dispersal and in biofilm resistance is not entirely clear, the use of QS inhibitors (QSI) has been proposed as a potential antibiofilm strategy. We have investigated whether QSI enhance the susceptibility of bacterial biofilms to treatment with conventional antimicrobial agents. The QSI used in our study target the acyl-homoserine lactone-based QS system present inPseudomonas aeruginosaandBurkholderia cepaciacomplex organisms (baicalin hydrate, cinnamaldehyde) or the peptide-based system present inStaphylococcus aureus(hamamelitannin). The effect of tobramycin (P. aeruginosa,B. cepaciacomplex) and clindamycin or vancomycin (S. aureus), alone or in combination with QSI, was evaluated in variousin vitroandin vivobiofilm model systems, including two invertebrate models and one mouse pulmonary infection model.In vitrothe combined use of an antibiotic and a QSI generally resulted in increased killing compared to killing by an antibiotic alone, although reductions were strain and model dependent. A significantly higher fraction of infectedGalleria mellonellalarvae andCaenorhabditis eleganssurvived infection following combined treatment, compared to treatment with an antibiotic alone. Finally, the combined use of tobramycin and baicalin hydrate reduced the microbial load in the lungs of BALB/c mice infected withBurkholderia cenocepaciamore than tobramycin treatment alone. Our data suggest that QSI may increase the success of antibiotic treatment by increasing the susceptibility of bacterial biofilms and/or by increasing host survival following infection.
Chemical Characterization and Biological Properties of NVC-422, a Novel, Stable
N
-Chlorotaurine Analog
Authors: Wang Lu , Belisle Barbara , Bassiri Mansour , Xu Ping , Debabov Dmitri , Celeri Chris , Alvarez Nichole , Robson Martin C. , Payne Wyatt G. , Najafi Ramin , Khosrovi Behzad 
Published: March 2011

ABSTRACT

During oxidative burst, neutrophils selectively generate HOCl to destroy invading microbial pathogens. Excess HOCl reacts with taurine, a semi-essential amino acid, resulting in the formation of the longer-lived biogenerated broad-spectrum antimicrobial agent,
N
-chlorotaurine (NCT). In the presence of an excess of HOCl or under moderately acidic conditions, NCT can be further chlorinated, or it can disproportionate to produce
N
,
N
-dichlorotaurine (NNDCT). In the present study, 2,2-dimethyltaurine was used to prepare a more stable
N
-chlorotaurine, namely,
N
,
N
-dichloro-2,2-dimethyltaurine (NVC-422). In addition, we report on the chemical characterization,
in vitro
antimicrobial properties, and cytotoxicity of this compound. NVC-422 was shown effectively to kill all 17 microbial strains tested, including antibiotic-resistant
Staphylococcus aureus
and
Enterococcus faecium
. The minimum bactericidal concentration of NVC-422 against Gram-negative and Gram-positive bacteria ranged from 0.12 to 4 μg/ml. The minimum fungicidal concentrations against
Candida albicans
and
Candida glabrata
were 32 and 16 μg/ml, respectively. NVC-422 has an
in vitro
cytotoxicity (50% cytotoxicity = 1,440 μg/ml) similar to that of NNDCT. Moreover, our data showed that this agent possesses rapid, pH-dependent antimicrobial activity. At pH 4, NVC-422 completely killed both
Escherichia coli
and
S. aureus
within 5 min at a concentration of 32 μg/ml. Finally, the effect of NVC-422 in the treatment of an
E. coli
-infected granulating wound rat model was evaluated. Treatment of the infected granulating wound with NVC-422 resulted in significant reduction of the bacterial tissue burden and faster wound healing compared to a saline-treated control. These findings suggest that NVC-422 could have potential application as a topical antimicrobial.
Synergistic Effect of 14-Alpha-Lipoyl Andrographolide and Various Antibiotics on the Formation of Biofilms and Production of Exopolysaccharide and Pyocyanin by Pseudomonas aeruginosa
Authors: Zeng Xiangping , Liu Xiangyang , Bian Jiang , Pei Gang , Dai Huanqin , Polyak Steven W. , Song Fuhang , Ma Li , Wang Yuqiang , Zhang Lixin 
Published: March 2011

ABSTRACT

Pseudomonas aeruginosa
produces a biofilm that provides the bacteria with an effective barrier against antibiotics. Here, we investigated the synergy of various antibiotics with 14-alpha-lipoyl andrographolide (AL-1), focusing upon synthesis of the biofilm. AL-1 also inhibited the production of the exopolysaccharide and pyocyanin components. We propose that AL-1 may potentially serve as a cotherapy to combat
P. aeruginosa
.
Effect of Antibiotic Treatment on Establishment and Elimination of Intestinal Colonization by KPC-Producing Klebsiella pneumoniae in Mice
Authors: Perez Federico , Pultz Michael J. , Endimiani Andrea , Bonomo Robert A. , Donskey Curtis J. 
Published: March 2011

ABSTRACT

An understanding of the impact of antibiotics on the intestinal reservoir of KPC carbapenemase-producing
Klebsiella pneumoniae
(KPC-Kp) is important to prevent its emergence. We used a mouse model to examine the effect of antibiotic treatment on the establishment and elimination of intestinal colonization with KPC-Kp. Mice (10 per group) received subcutaneous antibiotics daily for 8 days. On day 3 of treatment, 10
3
CFU of KPC-Kp was given orogastrically, and concentrations of KPC-Kp in stool were monitored. Additional experiments assessed the effects of antibiotic treatment on concentrations of total anaerobes and
Bacteroides
spp. in stool and the efficacy of orogastric gentamicin and polymyxin E in suppressing KPC-Kp colonization. Of four antibiotics with minimal activity against the KPC-Kp test strain (MIC ≥ 16 μg/ml), those that suppressed total anaerobes and bacteroides (i.e., clindamycin and piperacillin-tazobactam) promoted colonization by KPC-Kp (
P
< 0.001), whereas agents that did not suppress total anaerobes or bacteroides (i.e., ciprofloxacin and cefepime) did not (
P
= 0.35). Of two agents with moderate activity against the KPC-Kp test strain, ertapenem (MIC, 4 μg/ml) did not promote colonization by KPC-Kp, whereas tigecycline (MIC, 3 μg/ml) did (
P
< 0.001), despite not reducing levels of total anaerobes or bacteroides. Orogastric treatment with gentamicin and polymyxin E suppressed KPC-Kp to undetectable levels in the majority of mice. These data suggest that antibiotics that disturb the intestinal anaerobic microflora and lack significant activity against KPC-Kp promote colonization by this organism. The administration of nonabsorbed oral antibiotics may be an effective strategy to suppress colonization with KPC-Kp.
Multiple Origins of Plasmodium falciparum Dihydropteroate Synthetase Mutant Alleles Associated with Sulfadoxine Resistance in India
Authors: Lumb Vanshika , Das Manoj K. , Singh Neeru , Dev Vas , Khan Wajihullah , Sharma Yagya D. 
Published: March 2011

ABSTRACT

With the spread of chloroquine (CQ)-resistant malaria in India, sulfadoxine-pyrimethamine (SP) alone or in combination with artesunate is used as an alternative antimalarial drug. Due to continuous drug pressure, the
Plasmodium falciparum
parasite is exhibiting resistance to antifolates because of mutations in candidate genes dihydrofolate reductase (
dhfr
) and dihydropteroate synthetase (
dhps
). Our earlier study on flanking microsatellite markers of
dhfr
mutant alleles from India had shown a single origin of the pyrimethamine resistance and some minor haplotypes which shared haplotypes with Southeast Asian (Thailand) strains. In the present study, we have analyzed 193 of these Indian
P. falciparum
isolates for 15 microsatellite loci around
dhps
to investigate the genetic lineages of the mutant
dhps
alleles in different parts of the country. Eighty-one of these samples had mutant
dhps
alleles, of which 62 were from Andaman and Nicobar Islands and the remaining 19 were from mainland India. Of 112 isolates with a wild-type
dhps
allele, 109 were from mainland India and only 3 were from Andaman and Nicobar Islands. Consistent with the model of selection, the mean expected heterozygosity (

H
e

) around mutant
dhps
alleles (

H
e

= 0.55;
n
= 81) associated with sulfadoxine resistance was lower (
P
≤ 0.05) than the mean

H
e

around the wild-type
dhps
allele (

H
e

= 0.80;
n
= 112). There was more genetic diversity in flanking microsatellites of
dhps
than
dhfr
among these isolates, which confirms the assertion that
dhps
mutations are at a very early stage of fixation in the parasite population. Microsatellite haplotypes around various mutant
dhps
alleles suggest that the resistant
dhps
alleles have multiple independent origins in India, especially in Andaman and Nicobar Islands. Determining the genetic lineages of the resistant
dhps
alleles on Andaman and Nicobar Islands and mainland India is significant, given the role of Asia in the intercontinental spread of chloroquine- and pyrimethamine-resistant parasites in the past.
First Report of Klebsiella oxytoca Strain Coproducing KPC-2 and IMP-8 Carbapenemases
Authors: Li Bin , Sun Jing-Yong , Liu Qing-Zhong , Han Li-Zhong , Huang Xin-Hong , Ni Yu-Xing 
Published: March 2011

ABSTRACT

The study shows for the first time the presence of the
Klebsiella oxytoca
strain fp10 coproducing plasmid-mediated KPC-2 and IMP-8 carbapenemases. The strain was obtained from the fecal sample of an inpatient and showed high-level resistance to imipenem and ertapenem (MICs > 32 μg/ml). Conjugation experiments demonstrated the transferability of the carbapenem-resistant determinants. The results of plasmid analysis and Southern hybridization revealed that the
bla
KPC-2
gene was located on transferable plasmid pFP10-1 (∼54 kb), whereas the
bla
IMP-8
gene was on transferable plasmid pFP10-2 (∼180 kb). Analysis of the genetic environment of these two genes has demonstrated that IS
Kpn6
and IS
Kpn8
are involved in the spread of the
bla
KPC-2
gene, while the transposable elements IS
26
,
intI1
, and
tniC
might contribute to the dissemination of the
bla
IMP-8
gene. The chimera of several transposon-associated elements indicated a novel genetic environment of IMP-type metallo-β-lactamase gene in
Enterobacteriaceae
from China.
Mutation in the
sdeS
Gene Promotes Expression of the
sdeAB
Efflux Pump Genes and Multidrug Resistance in Serratia marcescens
Authors: Maseda Hideaki , Hashida Yumiko , Shirai Akihiro , Omasa Takeshi , Nakae Taiji 
Published: March 2011

ABSTRACT

Serratia marcescens
gained resistance to both biocides and antibiotics on expressing the SdeAB efflux pump, following exposure to increasingly higher concentrations of a biocide (H. Maseda et al., Antimicrob. Agents Chemother. 53:5230–5235, 2009). To reveal the regulatory mechanism of
sdeAB
expression, wild-type cells were subjected to transposon-mediated random mutagenesis, and a mutant with antibiotic resistance, which mimicked the phenotype of the previous biocide-resistant cells, was obtained. The transposon element was found in the chromosomal DNA downstream of the
sdeAB
operon. Sequencing revealed the presence of an open reading frame (ORF) encoding a protein with 159 amino acid residues that is highly similar to the BadM-type transcriptional repressor, designated
sdeS
. The level of
sdeB
::
xylE
reporter gene expression, undetectable in the wild-type cells, appeared to be fully comparable to that in the biocide-resistant cells. Nucleotide sequencing of the mutant revealed
sdeS
to have a single G-to-A base substitution at position 269 that converted Trp90 to a stop codon. Introduction of a plasmid-borne intact
sdeS
into the mutant cells and the biocide-resistant cells resulted in a reduction in
sdeB
::
xylE
reporter activity to an undetectable level. These results suggested that SdeS functions as a repressor of the
sdeAB
operon. It was concluded that the original biocide-resistant cells had an impaired
sdeS
and, therefore, a derepressed level of the SdeAB efflux pump.
Steady-State Plasma Pharmacokinetics of Oral Voriconazole in Obese Adults
Authors: Pai Manjunath P. , Lodise Thomas P. 
Published: March 2011

ABSTRACT

Voriconazole is an antifungal agent that is currently used as primary therapy for invasive aspergillosis and as a potential treatment for systemic candidiasis. Data on the dosing of voriconazole in obese patients are not available, which is problematic given the increased prevalence of this special population. To address this limitation, we evaluated the steady-state plasma pharmacokinetics of voriconazole through a two-way, crossover design in a cohort of eight healthy volunteers with class II obesity or greater. The median (minimum, maximum) age, weight, and body mass index of obese subjects were 43 (22, 48) years, 133 (105, 155) kg, and 46.2 (38.4, 53.7) kg/m
2
, respectively. The geometric mean ratios (90% confidence intervals) for the area under the curve from time zero to 12 h (dosing interval; AUC
0–τ
), maximum concentration (
C
max
), minimum concentration at 12 h (
C
min
), and time to
C
max
(
T
max
) of the 300-mg to 200-mg dosing regimens were 2.0 (1.5, 2.7), 1.8 (1.4, 2.2), 2.2 (1.6, 2.9), and 1.6 (1.0, 2.4) in obese subjects, respectively. The AUC
0–τ
values observed in obese subjects were comparable to those from a historical data set of nonobese subjects. Voriconazole dose-normalized AUC
0–τ
values had a modestly better correlation with lean body weight (
r
2
= 0.42) than total body weight (
r
2
= 0.14). An excellent linear relationship (
r
2
= 0.96) was identified between
C
min
values and AUC
0–τ
values. Adjustment of voriconazole doses in individuals with class II obesity or greater does not appear to be necessary on the basis of body weight.
Loss of Heterozygosity of
FCY2
Leading to the Development of Flucytosine Resistance in Candida tropicalis
Authors: Chen Yen-Ning , Lo Hsiu-Jung , Wu Chia-Chen , Ko Hui-Ching , Chang Te-Pin , Yang Yun-Liang 
Published: March 2011

ABSTRACT

As fluconazole resistance becomes an emerging issue for treating infections caused by
Candida tropicalis
, searching for alternative becomes a prominent task. In the present study, 97 clinical isolates of
C. tropicalis
were tested for the susceptibilities to flucytosine (5FC) with the Etest method. Although only one isolate was resistant to 5FC, 30 susceptible isolates could produce resistant progeny after exposure to the drug. Interestingly, 22 of these 30 clinical isolates had a heterozygous G/T at the 145th position on
FCY2
, encoding purine-cytosine permease, whereas their progeny recovered from within the inhibitory ellipses had homozygous T/T, resulting in null alleles for both copies of the gene and produced only truncated proteins, effecting the 5FC resistance. Furthermore, we found that two major fluconazole-resistant clinical clones, diploid sequence type 98 (DST98) and DST140, had a homozygous G/G at the 145th position, and neither was able to produce 5FC-resistant progeny within the inhibitory ellipses. Hence, strains of
C. tropicalis
containing heterozygous alleles may develop 5FC resistance readily, whereas those with homozygous G/G wild-type alleles can be treated with 5FC. Subsequently, a combination of 5FC and another antifungal drug is applicable for treating infections of
C. tropicalis
.
The Interaction between Candida krusei and Murine Macrophages Results in Multiple Outcomes, Including Intracellular Survival and Escape from Killing
Authors: García-Rodas Rocío , González-Camacho Fernando , Rodríguez-Tudela Juan Luis , Cuenca-Estrella Manuel , Zaragoza Oscar 
Published: March 2011

ABSTRACTCandida kruseiis a fungal pathogen of interest for the scientific community for its intrinsic resistance to fluconazole. Little is known about the interaction of this yeast with host immune cells. In this work, we have characterized the outcome of the interaction betweenC. kruseiand murine macrophages. OnceC. kruseiwas internalized, we observed different phenomena. In a macrophage-like cell line,C. kruseisurvived in a significant number of macrophages and induced filamentation and macrophage explosion. Phagocytosis ofC. kruseiled to actin polymerization around the yeast cells at the site of entry. Fluorescent specific staining with anti-Lamp1 and LysoTracker indicated that after fungal internalization, there was a phagolysosome maturation defect, a phenomenon that was more efficient when the macrophages phagocytosed killed yeast cells. Using cell line macrophages, we also observed macrophage fusion after cell division. When we used primary resident peritoneal macrophages in addition to macrophage explosion, we also observed a strong chemotaxis of uninfected macrophages to regions whereC. krusei-infected macrophages were present. We also noticed yeast transfer phenomena between infected macrophages. Primary macrophages inhibited pseudohypha elongation more efficiently than the macrophage-like cell line, suggesting thatC. kruseiinfection was better controlled by the former macrophages. Primary macrophages induced more tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) than the macrophage-like cell line. Our results demonstrate thatC. kruseican exploit the macrophages for replication, although other different outcomes are also possible, indicating that the interaction of this pathogen with phagocytic cells is very complex and regulated by multiple factors.
Identification of
In Vivo
-Induced Antigens Including an RTX Family Exoprotein Required for Uropathogenic Escherichia coli Virulence
Authors: Vigil Patrick D. , Alteri Christopher J. , Mobley Harry L. T. 
Published: March 2011

ABSTRACT

Uncomplicated urinary tract infections (UTI) are caused most commonly by uropathogenic
Escherichia coli
(UPEC). Whole-genome screening approaches, including transcriptomic, proteomic, and signature-tagged mutagenesis, have shown that UPEC highly expresses or requires genes for translational machinery, capsule, lipopolysaccharide, type 1 fimbriae, and iron acquisition systems during UTI. To identify additional genes expressed by UPEC during UTI, an immunoscreening approach termed
in vivo
-induced antigen technology (IVIAT) was employed to identify antigens produced during experimental infection that are not produced during
in vitro
culture. An inducible protein expression library, constructed from genomic DNA isolated from UPEC strain CFT073, was screened using exhaustively adsorbed pooled sera from 20 chronically infected female CBA/J mice. Using this approach, we identified 93 antigens induced by UPEC
in vivo
. A representative subset of these genes was tested by quantitative PCR for expression by CFT073
in vivo
and during growth in human urine or LB medium
in vitro
;
proWX
,
narJI
,
lolA
,
lolD
,
tosA
(
upxA
), c2432,
katG
,
ydhX
,
kpsS
, and
yddQ
were poorly expressed
in vitro
but highly expressed
in vivo
. Of these,
tosA
, a gene encoding a predicted repeat-in-toxin family member, was expressed exclusively during UTI. Deletion of
tosA
in UPEC strain CFT073 resulted in significant attenuation in bladder and kidney infections during ascending UTI. By screening for
in vivo
-induced antigens, we identified a novel UPEC virulence factor and additional proteins that could be useful as potential vaccine targets.
Deletion of a Cation Transporter Promotes Lysis in Streptococcus pneumoniae
Authors: Neef Jolanda , Andisi Vahid Farshchi , Kim Kwang S. , Kuipers Oscar P. , Bijlsma Jetta J. E. 
Published: March 2011

ABSTRACTStreptococcus pneumoniaeis a significant human pathogen which causes respiratory and serious invasive diseases. Mg2+is essential for life, and its concentration varies throughout the human body. Magnesium uptake plays an important role in the virulence of many bacterial pathogens. To study the Mg2+uptake ofS. pneumoniaestrain D39, a mutant was generated in SPD1383, a P-type ATPase with homology to theSalmonellaMg2+transporter MgtA, which has also been shown to be a Ca2+exporter in strain TIGR4. Under low-Ca2+conditions, mutation led to a growth defect in complex medium and the gene was nearly essential for growth under low-Mg2+conditions. Addition of Mg2+restored the normal growth of the mutant in all cases, but the addition of other divalent cations had no effect. Addition of Ca2+, Mn2+, and Zn2+in the presence of high Mg2+concentrations inhibited restoration of growth. The mutant was unable to proliferate in blood, which was also alleviated by the addition of Mg2+. The protein was located in the membrane and produced in variousS. pneumoniaestrains and pathogenic streptococcal species. Surprisingly, mutation of the gene led to an elevated toxicity for endothelial cells. This was caused by an increased amount of pneumolysin in the medium, mediated by elevated lysis of the mutant. Thus, in this study, we uncovered a role for SPD1383 in Mg2+uptake and hypothesize that the protein is a Mg2+/Ca2+antiporter. Furthermore, a disturbance in Mg2+homeostasis seems to promote lysis ofS. pneumoniae.
The Staphylococcus aureus KdpDE Two-Component System Couples Extracellular K
+
Sensing and Agr Signaling to Infection Programming
Authors: Xue Ting , You Yibo , Hong De , Sun Haipeng , Sun Baolin 
Published: March 2011

ABSTRACT

The Kdp system is widely distributed among bacteria. In
Escherichia coli
, the Kdp-ATPase is a high-affinity K
+
uptake system and its expression is activated by the KdpDE two-component system in response to K
+
limitation or salt stress. However, information about the role of this system in many bacteria still remains obscure. Here we demonstrate that KdpFABC in
Staphylococcus aureus
is not a major K
+
transporter and that the main function of KdpDE is not associated with K
+
transport but that instead it regulates transcription for a series of virulence factors through sensing external K
+
concentrations, indicating that this bacterium might modulate its infectious status through sensing specific external K
+
stimuli in different environments. Our results further reveal that
S. aureus
KdpDE is upregulated by the Agr/RNAIII system, which suggests that KdpDE may be an important virulence regulator coordinating the external K
+
sensing and Agr signaling during pathogenesis in this bacterium.