bluuebunny/crossref_metadata_2025_split huggingface dataset:
Siderophore Cephalosporin Cefiderocol Utilizes Ferric Iron Transporter Systems for Antibacterial Activity against Pseudomonas aeruginosa
Authors: Ito Akinobu , Nishikawa Toru , Matsumoto Shuhei , Yoshizawa Hidenori , Sato Takafumi , Nakamura Rio , Tsuji Masakatsu , Yamano Yoshinori 
Published: October 2016

ABSTRACT

Cefiderocol (S-649266) is a novel parenteral siderophore cephalosporin conjugated with a catechol moiety at the third-position side chain. The
in vitro
activity of cefiderocol against
Pseudomonas aeruginosa
was enhanced under iron-depleted conditions, whereas that of ceftazidime was not affected. The monitoring of [thiazole-
14
C]cefiderocol revealed the increased intracellular accumulation of cefiderocol in
P. aeruginosa
cells incubated under iron-depleted conditions compared with those incubated under iron-sufficient conditions. Cefiderocol was shown to have potent chelating activity with ferric iron, and extracellular iron was efficiently transported into
P. aeruginosa
cells in the presence of cefiderocol as well as siderophores, while enhanced transport of extracellular ferric iron was not observed when one of the hydroxyl groups of the catechol moiety of cefiderocol was replaced with a methoxy group. We conclude that cefiderocol forms a chelating complex with iron, which is actively transported into
P. aeruginosa
cells via iron transporters, resulting in potent antibacterial activity of cefiderocol against
P. aeruginosa
.
Design and Validation of Novel Chikungunya Virus Protease Inhibitors
Authors: Das Pratyush Kumar , Puusepp Laura , Varghese Finny S. , Utt Age , Ahola Tero , Kananovich Dzmitry G. , Lopp Margus , Merits Andres , Karelson Mati 
Published: October 2016

ABSTRACT

Chikungunya virus (CHIKV; genus
Alphavirus
) is the causative agent of chikungunya fever. CHIKV replication can be inhibited by some broad-spectrum antiviral compounds; in contrast, there is very little information about compounds specifically inhibiting the enzymatic activities of CHIKV replication proteins. These proteins are translated in the form of a nonstructural (ns) P1234 polyprotein precursor from the CHIKV positive-strand RNA genome. Active forms of replicase enzymes are generated using the autoproteolytic activity of nsP2. The available three-dimensional (3D) structure of nsP2 protease has made it a target for
in silico
drug design; however, there is thus far little evidence that the designed compounds indeed inhibit the protease activity of nsP2 and/or suppress CHIKV replication. In this study, a set of 12 compounds, predicted to interact with the active center of nsP2 protease, was designed using target-based modeling. The majority of these compounds were shown to inhibit the ability of nsP2 to process recombinant protein and synthetic peptide substrates. Furthermore, all compounds found to be active in these cell-free assays also suppressed CHIKV replication in cell culture, the 50% effective concentration (EC
50
) of the most potent inhibitor being ∼1.5 μM. Analysis of stereoisomers of one compound revealed that inhibition of both the nsP2 protease activity and CHIKV replication depended on the conformation of the inhibitor. Combining the data obtained from different assays also indicates that some of the analyzed compounds may suppress CHIKV replication using more than one mechanism.
Occurrences and Characterization of Antibiotic-Resistant Bacteria and Genetic Determinants of Hospital Wastewater in a Tropical Country
Authors: Le Thai-Hoang , Ng Charmaine , Chen Hongjie , Yi Xin Zhu , Koh Tse Hsien , Barkham Timothy Mark Sebastian , Zhou Zhi , Gin Karina Yew-Hoong 
Published: October 2016

ABSTRACT

Wastewater discharged from clinical isolation and general wards at two hospitals in Singapore was examined to determine the emerging trends of antibiotic resistance (AR). We quantified the concentrations of 12 antibiotic compounds by analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS), antibiotic-resistant bacteria (ARB), the class 1 integrase gene (
intI1
), and 16 antibiotic resistance genes (ARGs) that confer resistance to 10 different clinically relevant antibiotics. A subset of 119 antibiotic-resistant isolates were phylogenetically classified and tested for the presence of ARGs encoding resistance to β-lactam antibiotics (
bla
NDM
,
bla
KPC
,
bla
SHV
,
bla
CTX-M
), amikacin [
aac(6′)-Ib
], co-trimoxazole (
sul1
,
sul2
,
dfrA
), ciprofloxacin (
qnrA
,
qnrB
), and the
intI1
gene. Among these resistant isolates, 80.7% were detected with
intI1
and 66.4% were found to carry at least 1 of the tested ARGs. Among 3 sampled locations, the clinical isolation ward had the highest concentrations of ARB and the highest levels of ARGs linked to resistance to β-lactam (
bla
KPC
), co-trimoxazole (
sul1
,
sul2
,
dfrA
), amikacin [
aac(6′)-Ib
], ciprofloxacin (
qnrA
), and
intI1
. We found strong positive correlations (
P
< 0.05) between concentrations of bacteria resistant to meropenem, ceftazidime, amikacin, co-trimoxazole, and ciprofloxacin and abundances of
bla
KPC
,
aac(6′)-Ib
,
sul1
,
sul2
,
dfrA
,
qnrA
, and
intI1
genes.
Pharmacokinetics of Piperacillin in Critically Ill Australian Indigenous Patients with Severe Sepsis
Authors: Tsai Danny , Stewart Penelope , Goud Rajendra , Gourley Stephen , Hewagama Saliya , Krishnaswamy Sushena , Wallis Steven C. , Lipman Jeffrey , Roberts Jason A. 
Published: October 2016

ABSTRACTThere are no available pharmacokinetic data to guide piperacillin dosing in critically ill Australian Indigenous patients despite numerous reported physiological differences. This study aimed to describe the population pharmacokinetics of piperacillin in critically ill Australian Indigenous patients with severe sepsis. A population pharmacokinetic study of Indigenous patients with severe sepsis was conducted in a remote hospital intensive care unit. Plasma samples were collected over two dosing intervals and assayed by validated chromatography. Population pharmacokinetic modeling was conducted using Pmetrics. Nine patients were recruited, and a two-compartment model adequately described the data. The piperacillin clearance (CL), volume of distribution of the central compartment (Vc), and distribution rate constants from the central to the peripheral compartment and from the peripheral to the central compartment were 5.6 ± 3.2 liters/h, 14.5 ± 6.6 liters, 1.5 ± 0.4 h−1, and 1.8 ± 0.9 h−1, respectively, where CL andVcwere found to be described by creatinine clearance (CLCR) and total body weight, respectively. In this patient population, piperacillin demonstrated high interindividual pharmacokinetic variability. CLCRwas found to be the most important determinant of piperacillin pharmacokinetics.
Nonencapsulated Trichinella pseudospiralis Infection Impairs Follicular Helper T Cell Differentiation with Subclass-Selective Decreases in Antibody Responses
Authors: Asano Kazunobu , Wu Zhiliang , Srinontong Piyarat , Ikeda Takahide , Nagano Isao , Morita Hirokuyi , Maekawa Yoichi 
Published: October 2016

ABSTRACT

Infectious microorganisms often modify host immunity to escape from immune elimination.
Trichinella
is a unique nematode of the helminth family, whose members parasitize the muscle cells inside the host without robust eliminative reactions. There are several species of
Trichinella
; some develop in muscle cells that become encapsulated (e.g.,
Trichinella spiralis
) and others in cells that do not encapsulate (e.g.,
Trichinella
pseudospiralis
). It has already been established that
Trichinella
infection affects host immune responses in several experimental immune diseases in animal models; however, most of those studies were done using
T. spiralis
infection. As host immune responses to
T. spiralis
and
T. pseudospiralis
infections have been reported to be different, it is necessary to clarify how
T. pseudospiralis
infection influences the host immune responses. In this study, we investigated the influence on host humoral immunity in
T. pseudospiralis
-infected mice. We demonstrated that
T. pseudospiralis
infection decreased antigen-specific IgG2a and IgG2b antibody (Ab) production in mice immunized with a model antigen. This selective decrease in gamma interferon (IFN-γ)-dependent Ab production was not due to a decrease in IFN-γ production, and we instead found impaired follicular helper T (Tfh) cell differentiation. The affinity maturation of antigen-specific Ab tended to be delayed but was not significant in
T. pseudospiralis
-infected mice. We also observed that CD11b
+
spleen cells in
T. pseudospiralis
-infected mice expressed CD206 and PD-L2, the phenotype of which was M2 macrophages with weak production of interleukin-6 (IL-6), possibly resulting in impaired Tfh differentiation. Taken together, our results indicate that nonencapsulated
Trichinella
infection induces selective dampening in humoral immunity with the suppression of Tfh differentiation.
InlP, a New Virulence Factor with Strong Placental Tropism
Authors: Faralla Cristina , Rizzuto Gabrielle A. , Lowe David E. , Kim Byoungkwan , Cooke Cara , Shiow Lawrence R. , Bakardjiev Anna I. 
Published: October 2016

ABSTRACTIntrauterine infection is a major detriment for maternal-child health and occurs despite local mechanisms that protect the maternal-fetal interface from a wide variety of pathogens. The bacterial pathogenListeria monocytogenescauses spontaneous abortion, stillbirth, and preterm labor in humans and serves as a model for placental pathogenesis. Given the unique immunological environment of the maternal-fetal interface, we hypothesized that virulence determinants with placental tropism are required for infection of this tissue. We performed a genomic screen in pregnant guinea pigs that led to the identification of 201 listerial genes important for infection of the placenta but not maternal liver. Among these genes waslmrg1778(lmo2470), here namedinlP, predicted to encode a secreted protein that belongs to the internalin family. InlP is conserved in virulentL. monocytogenesstrains but absent inListeriaspecies that are nonpathogenic for humans. The intracellular life cycle ofL. monocytogenesdeficient ininlP(ΔinlP) was not impaired. In guinea pigs and mice, InlP increased the placental bacterial burden by a factor of 3 log10while having only a minor role in other maternal organs. Furthermore, the ΔinlPstrain was attenuated in intracellular growth in primary human placental organ cultures and trophoblasts. InlP is a novel virulence factor for listeriosis with a strong tropism for the placenta. This virulence factor represents a tool for the development of new modalities to prevent and treat infection-related pregnancy complications.
Coxiella burnetii Avirulent Nine Mile Phase II Induces Caspase-1-Dependent Pyroptosis in Murine Peritoneal B1a B Cells
Authors: Schoenlaub Laura , Cherla Rama , Zhang Yan , Zhang Guoquan 
Published: October 2016

ABSTRACT

Our recent study demonstrated that virulent
Coxiella burnetii
Nine Mile phase I (NMI) is capable of infecting and replicating within peritoneal B1a cells and that B1a cells play an important role in host defense against
C. burnetii
infection in mice. However, it remains unknown if avirulent Nine Mile phase II (NMII) can infect and replicate in B1a cells and whether NMI and NMII can differentially interact with B1a cells. In this study, we examined if NMI and NMII can differentially modulate host cell apoptotic signaling in B1a cells. The results showed that NMII induced dose-dependent cell death in murine peritoneal B1a cells but NMI did not, suggesting that NMI and NMII may differentially activate host cell apoptotic signaling in B1a cells. Western blotting indicated that NMII-induced B1a cell death was not dependent on either caspase-3 or PARP-1 cleavage, but cleavage of caspase-1 was detected in NMII-infected B1a cells. In addition, inhibition or deficiency of caspase-1 activity blocked NMII-induced B1a cell death. These results suggest that NMII induces a caspase-1-dependent pyroptosis in murine peritoneal B1a cells. We also found that heat-killed NMII and type 4 secretion system (T4SS) mutant NMII were unable to induce B1a cell death and that NMII infection did not induce cell death in peritoneal B1a cells from Toll-like receptor 2 (TLR-2)- or NLRP3 inflammasome-deficient mice. These data suggest that NMII-induced caspase-1-dependent pyroptosis may require its T4SS and activation of the TLR-2 and NLRP3 signaling pathways.
Exploring Hydrogenotrophic Methanogenesis: a Genome Scale Metabolic Reconstruction of Methanococcus maripaludis
Authors: Richards Matthew A. , Lie Thomas J. , Zhang Juan , Ragsdale Stephen W. , Leigh John A. , Price Nathan D. 
Published: October 2016

ABSTRACT

Hydrogenotrophic methanogenesis occurs in multiple environments, ranging from the intestinal tracts of animals to anaerobic sediments and hot springs. Energy conservation in hydrogenotrophic methanogens was long a mystery; only within the last decade was it reported that net energy conservation for growth depends on electron bifurcation. In this work, we focus on
Methanococcus maripaludis
, a well-studied hydrogenotrophic marine methanogen. To better understand hydrogenotrophic methanogenesis and compare it with methylotrophic methanogenesis that utilizes oxidative phosphorylation rather than electron bifurcation, we have built iMR539, a genome scale metabolic reconstruction that accounts for 539 of the 1,722 protein-coding genes of
M. maripaludis
strain S2. Our reconstructed metabolic network uses recent literature to not only represent the central electron bifurcation reaction but also incorporate vital biosynthesis and assimilation pathways, including unique cofactor and coenzyme syntheses. We show that our model accurately predicts experimental growth and gene knockout data, with 93% accuracy and a Matthews correlation coefficient of 0.78. Furthermore, we use our metabolic network reconstruction to probe the implications of electron bifurcation by showing its essentiality, as well as investigating the infeasibility of aceticlastic methanogenesis in the network. Additionally, we demonstrate a method of applying thermodynamic constraints to a metabolic model to quickly estimate overall free-energy changes between what comes in and out of the cell. Finally, we describe a novel reconstruction-specific computational toolbox we created to improve usability. Together, our results provide a computational network for exploring hydrogenotrophic methanogenesis and confirm the importance of electron bifurcation in this process.

IMPORTANCE
Understanding and applying hydrogenotrophic methanogenesis is a promising avenue for developing new bioenergy technologies around methane gas. Although a significant portion of biological methane is generated through this environmentally ubiquitous pathway, existing methanogen models portray the more traditional energy conservation mechanisms that are found in other methanogens. We have constructed a genome scale metabolic network of
Methanococcus maripaludis
that explicitly accounts for all major reactions involved in hydrogenotrophic methanogenesis. Our reconstruction demonstrates the importance of electron bifurcation in central metabolism, providing both a window into hydrogenotrophic methanogenesis and a hypothesis-generating platform to fuel metabolic engineering efforts.
Protein Synthesis during Germination: Shedding New Light on a Classical Question
Authors: Boone Tyler , Driks Adam 
Published: October 2016

ABSTRACT

Despite over a century of research into the mystery of bacterial spore dormancy and germination, a key question remains unresolved: is protein synthesis required for germination? The development of more sophisticated techniques for assessing and preventing protein synthesis has renewed interest in this long-standing question in recent years. In this issue, Korza et al. (G. Korza, B. Setlow, L. Rao, Q. Li, and P. Setlow, J. Bacteriol 198:3254–3264, 2016,
http://dx.doi.org/10.1128/JB.00583-16
) address this with a novel approach. We discuss their results in the context of recently published data.
Prosthetic Device Infections
Authors: Martinez Raquel M. , Bowen Thomas R. , Foltzer Michael A. 
Published: October 2016

ABSTRACT
The immunocompromised host is a particularly vulnerable population in whom routine and unusual infections can easily and frequently occur. Prosthetic devices are commonly used in these patients and the infections associated with those devices present a number of challenges for both the microbiologist and the clinician. Biofilms play a major role in device-related infections, which may contribute to failed attempts to recover organisms from routine culture methods. Moreover, device-related microorganisms can be difficult to eradicate by antibiotic therapy alone. Changes in clinical practice and advances in laboratory diagnostics have provided significant improvements in the detection and accurate diagnosis of device-related infections. Disruption of the bacterial biofilm plays an essential role in recovering the causative agent in culture. Various culture and nucleic acid amplification techniques are more accurate to guide directed treatment regimens. This chapter reviews the performance characteristics of currently available diagnostic assays and summarizes published guidelines, where available, for addressing suspected infected prosthetic devices.
Parasites
Authors: Theel Elitza S. , Pritt Bobbi S. 
Published: October 2016

ABSTRACT
Parasites are an important cause of human disease worldwide. The clinical severity and outcome of parasitic disease is often dependent on the immune status of the host. Specific parasitic diseases discussed in this chapter are amebiasis, giardiasis, cryptosporidiosis, cyclosporiasis, cystoisosporiasis, microsporidosis, granulomatous amebic encephalitis, toxoplasmosis, leishmaniasis, Chagas disease, malaria, babesiosis, strongyloidiasis, and scabies.
Selected Topics in Anaerobic Bacteriology
Authors: Church Deirdre L. 
Published: October 2016

ABSTRACTAlteration in the host microbiome at skin and mucosal surfaces plays a role in the function of the immune system, and may predispose immunocompromised patients to infection. Because obligate anaerobes are the predominant type of bacteria present in humans at skin and mucosal surfaces, immunocompromised patients are at increased risk for serious invasive infection due to anaerobes. Laboratory approaches to the diagnosis of anaerobe infections that occur due to pyogenic, polymicrobial, or toxin-producing organisms are described. The clinical interpretation and limitations of anaerobe recovery from specimens, anaerobe-identification procedures, and antibiotic-susceptibility testing are outlined. Bacteriotherapy following analysis of disruption of the host microbiome has been effective for treatment of refractory or recurrentClostridium difficileinfection, and may become feasible for other conditions in the future.
Mycobacteria
Authors: Simner Patricia J. , Woods Gail L. , Wengenack Nancy L. 
Published: October 2016

ABSTRACT

The immunocompromised host is at increased risk of
Mycobacterium tuberculosis
complex and nontuberculous mycobacteria infection. Although
Mycobacterium tuberculosis
complex is a significant mycobacterial pathogen, nontuberculous mycobacteria causes substantial disease in those with suppressed immune responses. Mycobacterial infections can cause significant morbidity and mortality in this patient population, and rapid identification and susceptibility testing of the mycobacterial species is paramount to patient management and outcomes. Mycobacterial diagnostics has undergone some significant advances in the last two decades with immunodiagnostics (interferon gamma release assay), microscopy (light-emitting diode), culture (automated broth-based systems), identification (direct PCR, sequencing and matrix-assisted laser-desorption ionization–time of flight mass spectrometry) and susceptibility testing (molecular detection of drug resistance from direct specimens or positive cultures). Employing the most rapid and sensitive methods in the mycobacterial laboratory will have a tremendous impact on patient care and, in the case of
Mycobacterium tuberculosis
complex, in the control of tuberculosis.
Genitourinary Tract Infections
Authors: Lanfranco Odaliz ABREU , Alangaden George J. 
Published: October 2016

ABSTRACT
Similarly to the general population, genitourinary tract infections are common conditions in theimmunocompromised host. They can be furthermore divided into infections of the urinary tract and genital tract infections. Transplant recipients are more likely to have infections of the urinary tract infections while persons with human immunodeficiency virus (HIV) are at higher risk for the second group of infections, especially sexually transmitted infections (STIs). Manifestations of these diseases can be associated with more complications and can be more severe. We provide an overview of manifestations, diagnosis, and management of these disorders.
Yeasts
Authors: Zhang Sean X. , Wiederhold Nathan P. 
Published: October 2016

ABSTRACT
Yeasts are unicellular organisms that reproduce mostly by budding and less often by fission. Most medically important yeasts originate from Ascomycota or Basidiomycota. Here, we review taxonomy, epidemiology, disease spectrum, antifungal drug susceptibility patterns of medically important yeast, laboratory diagnosis, and diagnostic strategies.
Comparative Microbial Genomics and Forensics
Authors: Massey Steven E. 
Published: October 2016

ABSTRACT
Forensic science concerns the application of scientific techniques to questions of a legal nature and may also be used to address questions of historical importance. Forensic techniques are often used in legal cases that involve crimes against persons or property, and they increasingly may involve cases of bioterrorism, crimes against nature, medical negligence, or tracing the origin of food- and crop-borne disease. Given the rapid advance of genome sequencing and comparative genomics techniques, we ask how these might be used to address cases of a forensic nature, focusing on the use of microbial genome sequence analysis. Such analyses rely on the increasingly large numbers of microbial genomes present in public databases, the ability of individual investigators to rapidly sequence whole microbial genomes, and an increasing depth of understanding of their evolution and function. Suggestions are made as to how comparative microbial genomics might be applied forensically and may represent possibilities for the future development of forensic techniques. A particular emphasis is on the nascent field of genomic epidemiology, which utilizes rapid whole-genome sequencing to identify the source and spread of infectious outbreaks. Also discussed is the application of comparative microbial genomics to the study of historical epidemics and deaths and how the approaches developed may also be applicable to more recent and actionable cases.
Soil Microbial Forensics
Authors: Santiago-Rodriguez Tasha M. , Cano Raúl J. 
Published: October 2016

ABSTRACT
Soil microbial forensics can be defined as the study of how microorganisms can be applied to forensic investigations. The field of soil microbial forensics is of increasing interest and applies techniques commonly used in diverse disciplines in order to identify microbes and determine their abundances, complexities, and interactions with soil and surrounding objects. Emerging new techniques are also providing insights into the complexity of microbes in soil. Soil may harbor unique microbes that may reflect specific physical and chemical characteristics indicating site specificity. While applications of some of these techniques in the field of soil microbial forensics are still in early stages, we are still gaining insight into how microorganisms may be more robustly used in forensic investigations.