bluuebunny/crossref_metadata_2025_split huggingface dataset:
Descendents on local curves: rationality
Authors: Pandharipande R. , Pixton A. 
Published: November 2012

AbstractWe study the stable pairs theory of local curves in 3-folds with descendent insertions. The rationality of the partition function of descendent invariants is established for the full local curve geometry (equivariant with respect to the scaling 2-torus), including relative conditions and odd-degree insertions for higher-genus curves. The capped 1-leg descendent vertex (equivariant with respect to the 3-torus) is also proven to be rational. The results are obtained by combining geometric constraints with a detailed analysis of the poles of the descendent vertex.
Characterization of OXA-204, a Carbapenem-Hydrolyzing Class D β-Lactamase from Klebsiella pneumoniae
Authors: Potron Anaïs , Nordmann Patrice , Poirel Laurent 
Published: November 2012

ABSTRACT

A
Klebsiella pneumoniae
clinical isolate recovered in Tunisia showed resistance to all β-lactams and decreased susceptibility to carbapenems.
K. pneumoniae
204 expressed the carbapenem-hydrolyzing β-lactamase OXA-204, differing from OXA-48 by two amino acid substitutions (Gln98His and Thr99Arg) (class D β-lactamase [DBL] numbering). OXA-48 and OXA-204 shared similar resistance profiles, hydrolyzing carbapenems but sparing broad-spectrum cephalosporins. The
bla
OXA-204
gene was located on a ca. 150-kb IncA/C-type plasmid, which also carried the
bla
CMY-4
gene. The
bla
OXA-204
gene was associated with an IS
Ecp1
element, whereas the
bla
OXA-48
genes are usually associated with IS
1999
.
Relative to Quinine and Quinidine, Their 9-Epimers Exhibit Decreased Cytostatic Activity and Altered Heme Binding but Similar Cytocidal Activity versus Plasmodium falciparum
Authors: Gorka Alexander P. , Sherlach Katy S. , de Dios Angel C. , Roepe Paul D. 
Published: November 2012

ABSTRACT

The 9-epimers of quinine (QN) and quinidine (QD) are known to exhibit poor cytostatic potency against
P. falciparum
(Karle JM, Karle IL, Gerena L, Milhous WK, Antimicrob. Agents Chemother. 36:1538–1544, 1992). We synthesized 9-
epi
-QN (eQN) and 9-
epi
-QD (eQD) via Mitsunobu esterification-saponification and evaluated both cytostatic and cytocidal antimalarial activities. Relative to the cytostatic activity of QN and QD, we observed a large decrease in cytostatic activity (higher 50% inhibitory concentration [IC
50
s]) against QN-sensitive strain HB3, QN-resistant strain Dd2, and QN-hypersensitive strain K76I, consistent with previous work. However, we observed relatively small changes in cytocidal activity (the 50% lethal dose), similar to observations with chloroquine (CQ) analogues with a wide range of IC
50
s (see the accompanying paper [
A. P. Gorka, J. N. Alumasa, K. S. Sherlach, L. M. Jacobs, K. B. Nickley, J. P. Brower, A. C. de Dios, and P. D. Roepe
, Antimicrob. Agents Chemother. 57:356–364, 2013]). Compared to QN and QD, the 9-epimers had significantly reduced hemozoin inhibition efficiency and did not affect pH-dependent aggregation of ferriprotoporphyrin IX (FPIX) heme. Magnetic susceptibility measurements showed that the 9-epimers perturb FPIX monomer-dimer equilibrium in favor of monomer, and UV-visible (VIS) titrations showed that eQN and eQD bind monomer with similar affinity relative to QN and QD. However, unique ring proton shifts in the presence of zinc(II) protoporphyrin IX (ZnPIX) indicate that binding of the 9-epimers to monomeric heme is via a distinct geometry. We isolated eQN- and eQD-FPIX complexes formed under aqueous conditions and analyzed them by mass, fluorescence, and UV-VIS spectroscopies. The 9-epimers produced low-fluorescent adducts with a 2:1 stoichiometry (drug to FPIX) which did not survive electrospray ionization, in contrast to QN and QD complexes. The data offer important insight into the relevance of heme interactions as a drug target for cytostatic versus cytocidal dosages of quinoline antimalarial drugs and further elucidate a surprising structural diversity of quinoline antimalarial drug-heme complexes.
Characterization of Recombinant Fluoroquinolone-Resistant Pneumococcus-Like Isolates
Authors: Balsalobre Luz , Ortega Montserrat , de la Campa Adela G. 
Published: November 2012

ABSTRACT

Fourteen fluoroquinolone-resistant streptococcal isolates with recombinant DNA topoisomerase genes, preliminarily identified as pneumococci, were further characterized using phenotypic and genotypic approaches. Phenotypic tests classified them as atypical pneumococci. Phylogenetic relationships were analyzed by using the sequences of seven housekeeping alleles from these isolates and from isolates of
Streptococcus pneumoniae
,
Streptococcus mitis
,
Streptococcus oralis
, and
Streptococcus pseudopneumoniae
. Four isolates grouped with
S. pneumoniae
, seven grouped with
S. pseudopneumoniae
, and three grouped with
S. mitis
. These results generally agreed with those obtained with an optochin susceptibility test and with the organization of the
atp
operon chromosomal region, encoding the F
o
F
1
H
+
-ATPase (the target of optochin). All seven isolates grouping with
S. pseudopneumoniae
share the same
spr1368-atpC-atpA
gene order; all four grouping with
S. pneumoniae
share the
spr1368
-IS
1239-atpC-atpA
order, and two out of the three grouping with
S. mitis
share the
spr1284-atpC-atpA
order. In addition, evidence for recombination within the seven housekeeping alleles of the
S. pseudopneumoniae
population was provided by several methods: the index of association (0.4598,
P
< 0.001), the pairwise homoplasy index, and the split-decomposition method. This study confirms the existence of pneumococci among the alpha-hemolytic streptococci with DNA topoisomerase genes showing a mosaic structure and reveals a close relationship between atypical pneumococci and
S. pseudopneumoniae
.
Inhibition of 3-Hydroxy-3-Methylglutaryl–Coenzyme A Reductase and Application of Statins as a Novel Effective Therapeutic Approach against Acanthamoeba Infections
Authors: Martín-Navarro Carmen María , Lorenzo-Morales Jacob , Machin Rubén P. , López-Arencibia Atteneri , García-Castellano José Manuel , de Fuentes Isabel , Loftus Brendan , Maciver Sutherland K. , Valladares Basilio , Piñero José E. 
Published: November 2012

ABSTRACT

Acanthamoeba
is an opportunistic pathogen in humans, whose infections most commonly manifest as
Acanthamoeba
keratitis or, more rarely, granulomatous amoebic encephalitis. Although there are many therapeutic options for the treatment of
Acanthamoeba
, they are generally lengthy and/or have limited efficacy. Therefore, there is a requirement for the identification, validation, and development of novel therapeutic targets against these pathogens. Recently, RNA interference (RNAi) has been widely used for these validation purposes and has proven to be a powerful tool for
Acanthamoeba
therapeutics. Ergosterol is one of the major sterols in the membrane of
Acanthamoeba
. 3-Hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase is an enzyme that catalyzes the conversion of HMG-CoA to mevalonate, one of the precursors for the production of cholesterol in humans and ergosterol in plants, fungi, and protozoa. Statins are compounds which inhibit this enzyme and so are promising as chemotherapeutics. In order to validate whether this enzyme could be an interesting therapeutic target in
Acanthamoeba
, small interfering RNAs (siRNAs) against HMG-CoA were developed and used to evaluate the effects induced by the inhibition of
Acanthamoeba
HMG-CoA. It was found that HMG-CoA is a potential drug target in these pathogenic free-living amoebae, and various statins were evaluated
in vitro
against three clinical strains of
Acanthamoeba
by using a colorimetric assay, showing important activities against the tested strains. We conclude that the targeting of HMG-CoA and
Acanthamoeba
treatment using statins is a novel powerful treatment option against
Acanthamoeba
species in human disease.
Pharmacodynamics of Anidulafungin against Clinical Aspergillus fumigatus Isolates in a Nonneutropenic Murine Model of Disseminated Aspergillosis
Authors: Seyedmousavi Seyedmojtaba , Brüggemann Roger J. M. , Melchers Willem J. G. , Verweij Paul E. , Mouton Johan W. 
Published: November 2012

ABSTRACT

Azole resistance is an emerging increasing problem in
Aspergillus fumigatus
that results in treatment failure. Alternative treatments may improve the therapeutic outcome in patients with azole-resistant invasive aspergillosis (IA). Little is known about the
in vivo
efficacy of the echinocandin anidulafungin (AFG) in IA. The
in vivo
efficacy of 2.5, 5, 10, and 20 mg/kg of body weight AFG was assessed against two clinical
Aspergillus fumigatus
isolates with identical AFG minimum effective concentrations (MECs; 0.03 mg/liter) in a murine model of IA: a wild-type voriconazole (VCZ)-susceptible (VCZ
s
)
A. fumigatus
isolate (AZN 8196) and a VCZ-resistant (VCZ
r
)
A. fumigatus
isolate (V52-35) harboring the TR
34
/L98H resistance mechanism (substitution at codon L98 in combination with a 34-bp tandem repeat in the promoter region of the
CYP51A
gene). The pharmacokinetics of AFG were also assessed for each dose. Increasing doses increased survival for both isolates in a manner dependent on the AFG dose level (
R
2
= 0.99 and 0.95, respectively) up to a maximum of 72.7% and 45.45% for the VCZ
s
and VCZ
r
isolates, respectively. The area under the concentration-time curve (AUC) correlated significantly with the dose in a linear fashion over the entire dosing range (
R
2
= 0.86). The Hill equation with a variable slope fitted the relationship between the 24-h AUC/MEC ratio and 14-day survival well (
R
2
= 0.87;
P
< 0.05). The 50% effective AUC/MEC for total AFG was 126.5 (95% confidence interval, 79.09 to 202.03). AFG treatment improved the survival of mice in a dose-dependent manner; however, a maximal response was not achieved with either isolate even in those treated with the highest AFG dose.
Whole-Genome Analysis of a Daptomycin-Susceptible Enterococcus faecium Strain and Its Daptomycin-Resistant Variant Arising during Therapy
Authors: Tran Truc T. , Panesso Diana , Gao Hongyu , Roh Jung H. , Munita Jose M. , Reyes Jinnethe , Diaz Lorena , Lobos Elizabeth A. , Shamoo Yousif , Mishra Nagendra N. , Bayer Arnold S. , Murray Barbara E. , Weinstock George M. , Arias Cesar A. 
Published: November 2012

ABSTRACT

Development of daptomycin (DAP) resistance in
Enterococcus faecalis
has recently been associated with mutations in genes encoding proteins with two main functions: (i) control of the cell envelope stress response to antibiotics and antimicrobial peptides (LiaFSR system) and (ii) cell membrane phospholipid metabolism (glycerophosphoryl diester phosphodiesterase and cardiolipin synthase [
cls
]). However, the genetic bases for DAP resistance in
Enterococcus faecium
are unclear. We performed whole-genome comparative analysis of a clinical strain pair, DAP-susceptible
E. faecium
S447 and its DAP-resistant derivative R446, which was recovered from a single patient during DAP therapy. By comparative whole-genome sequencing, DAP resistance in R446 was associated with changes in 8 genes. Two of these genes encoded proteins involved in phospholipid metabolism: (i) an R218Q substitution in Cls and (ii) an A292G reversion in a putative cyclopropane fatty acid synthase enzyme. The DAP-resistant derivative R446 also exhibited an S333L substitution in the putative histidine kinase YycG, a member of the YycFG system, which, similar to LiaFSR, has been involved in cell envelope homeostasis and DAP resistance in other Gram-positive cocci. Additional changes identified in
E. faecium
R446 (DAP resistant) included two putative proteins involved in transport (one for carbohydrate and one for sulfate) and three enzymes predicted to play a role in general metabolism. Exchange of the “susceptible”
cls
allele from S447 for the “resistant” one belonging to R446 did not affect DAP susceptibility. Our results suggest that, apart from the LiaFSR system, the essential YycFG system is likely to be an important mediator of DAP resistance in some
E. faecium
strains.
Low-Level Persistence of Drug Resistance Mutations in Hepatitis B Virus-Infected Subjects with a Past History of Lamivudine Treatment
Authors: Margeridon-Thermet Severine , Svarovskaia Evguenia S. , Babrzadeh Farbod , Martin Ross , Liu Tommy F. , Pacold Mary , Reuman Elizabeth C. , Holmes Susan P. , Borroto-Esoda Katyna , Shafer Robert W. 
Published: November 2012

ABSTRACTWe sought to determine the prevalence of hepatitis B virus (HBV) lamivudine (LAM)-resistant minority variants in subjects who once received LAM but had discontinued it prior to virus sampling. We performed direct PCR Sanger sequencing and ultradeep pyrosequencing (UDPS) of HBV reverse transcriptase (RT) of plasma viruses from 45 LAM-naive subjects and 46 LAM-experienced subjects who had discontinued LAM a median of 24 months earlier. UDPS was performed to a depth of ∼3,000 reads per nucleotide. Minority variants were defined as differences from the Sanger sequence present in ≥0.5% of UDPS reads in a sample. Sanger sequencing identified ≥1 LAM resistance mutations (rtL80I/V, rtM204I, and rtA181T) in samples from 5 (11%) of 46 LAM-experienced and none of 45 LAM-naive subjects (0%;P= 0.06). UDPS detected ≥1 LAM resistance mutations (rtL80I/V, rtV173L, rtL180M, rtA181T, and rtM204I/V) in 10 (22%) of the 46 LAM-experienced subjects, including 5 in whom LAM resistance mutations were not identified by Sanger sequencing. Overall, LAM resistance mutations were more likely to be present in LAM-experienced (10/46, 22%) than LAM-naive subjects (0/45, 0%;P= 0.001). The median time since LAM discontinuation was 12.8 months in the 10 subjects with a LAM resistance mutation compared to 30.5 months in the 36 LAM-experienced subjects without a LAM resistance mutation (P< 0.001). The likelihood of detecting a LAM resistance mutation was significantly increased using UDPS compared to Sanger sequencing and was inversely associated with the time since LAM discontinuation.
In Vitro
Activity and Durability of a Combination of an Antibiofilm and an Antibiotic against Vascular Catheter Colonization
Authors: Mansouri Mohammad D. , Hull Richard A. , Stager Charles E. , Cadle Richard M. , Darouiche Rabih O. 
Published: November 2012

ABSTRACT

Catheter-associated infections can cause severe complications and even death. Effective antimicrobial modification of catheters that can prevent device colonization has the potential of preventing clinical infection. We studied
in vitro
the antimicrobial activities of central venous catheters impregnated with
N
-acetylcysteine (NAC), an antibiofilm agent, and a broad-spectrum antibiotic against a range of important clinical pathogens. NAC-levofloxacin-impregnated (NACLEV) catheters were also evaluated for their antiadherence activity. NACLEV catheters produced the most active and durable antimicrobial effect against both Gram-positive and Gram-negative isolates and significantly reduced colonization (
P
< 0.0001) by all tested pathogens compared to control catheters. These
in vitro
results suggest that this antimicrobial combination can potentially be used to combat catheter colonization and catheter-associated infection.
Cytostatic versus Cytocidal Activities of Chloroquine Analogues and Inhibition of Hemozoin Crystal Growth
Authors: Gorka Alexander P. , Alumasa John N. , Sherlach Katy S. , Jacobs Lauren M. , Nickley Katherine B. , Brower Jonathan P. , de Dios Angel C. , Roepe Paul D. 
Published: November 2012

ABSTRACT

We report an improved, nonhazardous, high-throughput assay for
in vitro
quantification of antimalarial drug inhibition of β-hematin (hemozoin) crystallization performed under conditions that are more physiological relative to previous assays. The assay uses the differential detergent solubility of crystalline and noncrystalline forms of heme and is optimized via the use of lipid catalyst. Using this assay, we quantify the effect of pH on the crystal growth-inhibitory activities of current quinoline antimalarials, evaluate the catalytic efficiencies of different lipids, and test for a possible correlation between hemozoin inhibition by drugs versus their antiplasmodial activity. Consistent with several previous reports, we found a good correlation between hemozoin inhibition potency versus cytostatic antiplasmodial potency (50% inhibitory concentration) for a series of chloroquine (CQ) analogues. However, we found no correlation between hemozoin inhibition potency and cytocidal antiplasmodial potency (50% lethal dose) for the same drugs, suggesting that cellular targets for these two layers of 4-aminoquinoline drug activity differ. This important concept is also explored further for QN and its stereoisomers in the accompanying paper (
A. P. Gorka, K. S. Sherlach, A. C. de Dios, and P. D. Roepe
, Antimicrob. Agents Chemother. 57:365–374, 2013).
GES-18, a New Carbapenem-Hydrolyzing GES-Type β-Lactamase from Pseudomonas aeruginosa That Contains Ile80 and Ser170 Residues
Authors: Bebrone Carine , Bogaerts Pierre , Delbrück Heinrich , Bennink Sandra , Kupper Michaël B. , Rezende de Castro Roberta , Glupczynski Youri , Hoffmann Kurt M. 
Published: November 2012

ABSTRACT

A clinical isolate of
Pseudomonas aeruginosa
recovered from the lower respiratory tract of an 81-year-old patient hospitalized in Belgium was sent to the national reference center to determine its resistance mechanism. PCR sequencing identified a new GES variant, GES-18, which differs from the carbapenem-hydrolyzing enzyme GES-5 by a single amino acid substitution (Val80Ile, in the numbering according to Ambler) and from GES-1 by two substitutions (Val80Ile and Gly170Ser). Detailed kinetic characterization showed that GES-18 and GES-5 hydrolyze imipenem and cefoxitin with similar kinetic parameters and that GES-18 was less susceptible than GES-1 to classical β-lactamase inhibitors such as clavulanate and tazobactam. The overall structure of GES-18 is similar to the solved structures of GES-1 and GES-2, the Val80Ile and Gly170Ser substitutions causing only subtle local rearrangements. Notably, the hydrolytic water molecule and the Glu166 residue were slightly displaced compared to their counterparts in GES-1. Our kinetic and crystallographic data for GES-18 highlight the pivotal role of the Gly170Ser substitution which distinguishes GES-5 and GES-18 from GES-1.
Novel Apidaecin 1b Analogs with Superior Serum Stabilities for Treatment of Infections by Gram-Negative Pathogens
Authors: Berthold Nicole , Czihal Patricia , Fritsche Stefanie , Sauer Ute , Schiffer Guido , Knappe Daniel , Alber Gottfried , Hoffmann Ralf 
Published: November 2012

ABSTRACT

Proline-rich antimicrobial peptides (PrAMPs) from insects and mammals have recently been evaluated for their pharmaceutical potential in treating systemic bacterial infections. Besides the native peptides, several shortened, modified, or even artificial sequences were highly effective in different murine infection models. Most recently, we showed that the 18-residue-long peptide Api88, an optimized version of apidaecin 1b, was efficient in two different animal infection models using the pathogenic
Escherichia coli
strains ATCC 25922 and Neumann, with a promising safety margin. Here, we show that Api88 is degraded relatively fast upon incubation with mouse serum, by cleavage of the C-terminal leucine residue. To improve its
in vitro
characteristics, we aimed to improve its serum stability. Replacing the C-terminal amide by the free acid or substituting Arg-17 with
l
-ornithine or
l
-homoarginine increased the serum stabilities by more than 20-fold (half-life, ∼4 to 6 h). These analogs were nontoxic to human embryonic kidney (HEK 293), human hepatoma (HepG2), SH-SY5Y, and HeLa cells and nonhemolytic to human erythrocytes. The binding constants of all three analogs with the chaperone DnaK, which is proposed as the bacterial target of PrAMPs, were very similar to that of Api88. Of all the analogs tested, Api137 (Gu-ONNRPVYIPRPRPPHPRL; Gu is
N
,
N
,
N
′,
N
′-tetramethylguanidino) appeared most promising due to its high antibacterial activity, which was very similar to Api88. Positional alanine and
d
-amino acid scans of Api137 indicated that substitutions of residues 1 to 13 had only minor effects on the activity against an
E. coli
strain, whereas substitutions of residues 14 to 18 decreased the activity dramatically. Based on the significantly improved resistance to proteolysis, Api137 appears to be a very promising lead compound that should be even more efficient
in vivo
than Api88.
Point Mutations within the Fatty Acid Synthase Type II Dehydratase Components HadA or HadC Contribute to Isoxyl Resistance in Mycobacterium tuberculosis
Authors: Gannoun-Zaki Laila , Alibaud Laeticia , Kremer Laurent 
Published: November 2012

ABSTRACT

The mechanism by which the antitubercular drug isoxyl (ISO) inhibits mycolic acid biosynthesis has not yet been reported. We found that point mutations in either the HadA or HadC component of the type II fatty acid synthase (FAS-II) are associated with increased levels of resistance to ISO in
Mycobacterium tuberculosis
. Overexpression of the HadAB, HadBC, or HadABC heterocomplex also produced high-level resistance. These results show that the FAS-II dehydratases are involved in ISO resistance.
Outcome of Debridement and Retention in Prosthetic Joint Infections by Methicillin-Resistant Staphylococci, with Special Reference to Rifampin and Fusidic Acid Combination Therapy
Authors: Peel T. N. , Buising K. L. , Dowsey M. M. , Aboltins C. A. , Daffy J. R. , Stanley P. A. , Choong P. F. M. 
Published: November 2012

ABSTRACT

The management of prosthetic joint infections remains a clinical challenge, particularly infections due to methicillin-resistant staphylococci. Previously, this infection was considered a contraindication to debridement and retention strategies. This retrospective cohort study examined the treatment and outcomes of patients with arthroplasty infection by methicillin-resistant staphylococci managed by debridement and retention in conjunction with rifampin-fusidic acid combination therapy. Over an 11-year period, there were 43 patients with infection by methicillin-resistant staphylococci managed with debridement and retention. This consisted of close-interval repeated arthrotomies with pulsatile lavage. Rifampin was combined with fusidic acid for the majority of patients (88%). Patients were monitored for a median of 33.5 months (interquartile range, 20 to 54 months). Overall, 9 patients experienced treatment failure, with 12- and 24-month estimates of infection-free survival of 86% (95% confidence interval [CI], 71 to 93%) and 77% (95% CI, 60 to 87%), respectively. The following factors were associated with treatment failure: methicillin-resistant
Staphylococcus aureus
(MRSA) arthroplasty infection, a single surgical debridement or ≥4 debridements, and the receipt of less than 90 days of antibiotic therapy. Patients with infection by methicillin-resistant coagulase-negative staphylococci (MR-CNS) were less likely to fail treatment. The overall treatment success rate reported in this study is comparable to those of other treatment modalities for prosthetic joint infections by methicillin-resistant staphylococci. Therefore, the debridement and retention of the prosthesis and rifampin-based antibiotic therapy are a valid treatment option for carefully selected patients.
Additional Diagnostic Yield of Adding Serology to PCR in Diagnosing Viral Acute Respiratory Infections in Kenyan Patients 5 Years of Age and Older
Authors: Feikin Daniel R. , Njenga M. Kariuki , Bigogo Godfrey , Aura Barrack , Gikunju Stella , Balish Amanda , Katz Mark A. , Erdman Dean , Breiman Robert F. 
Published: November 2012

ABSTRACT
The role of serology in the setting of PCR-based diagnosis of acute respiratory infections (ARIs) is unclear. We found that acute- and convalescent-phase paired-sample serologic testing increased the diagnostic yield of naso/oropharyngeal swabs for influenza virus, respiratory syncytial virus (RSV), human metapneumovirus, adenovirus, and parainfluenza viruses beyond PCR by 0.4% to 10.7%. Although still limited for clinical use, serology, along with PCR, can maximize etiologic diagnosis in epidemiologic studies.