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ACS Infectious Diseases

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https://www.readbyqxmd.com/read/28591513/unravelling-the-molecular-basis-of-high-affinity-nanobodies-against-hiv-p24-in-vitro-functional-structural-and-in-silico-insights
#1
Eleanor R Gray, Jennifer C Brookes, Christophe Caillat, Valérian Turbé, Benjamin L J Webb, Luke A Granger, Benjamin S Miller, Laura E McCoy, Mohamed El Khattabi, C Theo Verrips, Robin A Weiss, Dorothy M Duffy, Winfried Weissenhorn, Rachel A McKendry
Preventing the spread of infectious diseases remains an urgent priority worldwide, and this is driving the development of advanced nanotechnology to diagnose infections at the point of care. Herein, we report the creation of a library of novel nanobody capture ligands to detect p24, one of the earliest markers of HIV infection. We demonstrate that these nanobodies, one tenth the size of conventional antibodies, exhibit high sensitivity and broad specificity to global HIV-1 subtypes. Biophysical characterization indicates strong 690 pM binding constants and fast kinetic on-rates, 1 to 2 orders of magnitude better than monoclonal antibody comparators...
June 26, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28636325/challenges-and-hallmarks-of-establishing-alkylacetylphosphonates-as-probes-of-bacterial-1-deoxy-d-xylulose-5-phosphate-synthase
#2
Sara Sanders, Ryan J Vierling, David Bartee, Alicia A DeColli, Mackenzie J Harrison, Joseph L Aklinski, Andrew T Koppisch, Caren L Freel Meyers
1-Deoxy-d-xylulose 5-phosphate (DXP) synthase catalyzes the thiamin diphosphate (ThDP)-dependent formation of DXP from pyruvate and d-glyceraldehyde 3-phosphate. DXP is at a metabolic branch point in bacteria, feeding into the methylerythritol phosphate pathway to indispensable isoprenoids and acting as a precursor for biosynthesis of essential cofactors in central metabolism, pyridoxal phosphate and ThDP, the latter of which is also required for DXP synthase catalysis. DXP synthase follows a unique random sequential mechanism and possesses an unusually large active site...
June 21, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28585815/neisseria-gonorrhoeae-lytic-transglycosylases-ltga-and-ltgd-reduce-host-innate-immune-signaling-through-tlr2-and-nod2
#3
Kayla J Knilans, Kathleen T Hackett, James E Anderson, Chengyu Weng, Joseph P Dillard, Joseph A Duncan
Neisseria gonorrhoeae releases anhydro peptidoglycan monomers during growth through the action of two lytic transglycosylases encoded in the N. gonorrhoeae genome, LtgA and LtgD. Because peptidoglycan and peptidoglycan components activate innate immune signaling, we hypothesized that the activity of LtgA and LtgD would influence the host responses to gonococcal infection. N. gonorrhoeae lacking LtgA and LtgD caused increased host production of inflammatory cytokines IL-1β and TNF-α. Culture supernatants from ΔltgA/ΔltgD N...
June 21, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28605587/allosteric-regulation-of-phosphatidylinositol-4-kinase-iii-beta-by-an-anti-picornavirus-compound-mdl-860
#4
Minetaro Arita, Georgi Dobrikov, Gerhard Pürstinger, Angel Galabov
MDL-860 is a broad-spectrum anti-picornavirus compound discovered in 1982, and one of the few promising candidates effective in in vivo virus infection. Despite the effectiveness, the target and the mechanism of action of MDL-860 remain unknown. Here, we have characterized anti-poliovirus activity of MDL-860, and identified host phosphatidylinositol-4 kinase III beta (PI4KB) as the target. MDL-860 treatment caused covalent modification and irreversible inactivation of PI4KB. A cysteine residue at amino acid 646 of PI4KB, which locates at the bottom of a surface pocket apart from the active site, was identified as the target site of MDL-860...
June 12, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28551989/optimized-fluorescence-complementation-platform-for-visualizing-salmonella-effector-proteins-reveals-distinctly-different-intracellular-niches-in-different-cell-types
#5
Alexandra M Young, Michael Minson, Sarah E McQuate, Amy E Palmer
The bacterial pathogen Salmonella uses sophisticated type III secretion systems (T3SS) to translocate and deliver bacterial effector proteins into host cells to establish infection. Monitoring these important virulence determinants in the context of live infections is a key step in defining the dynamic interface between the host and pathogen. Here, we provide a modular labeling platform based on fluorescence complementation with split-GFP that permits facile tagging of new Salmonella effector proteins. We demonstrate enhancement of split-GFP complementation signals by manipulating the promoter or by multimerizing the fluorescent tag and visualize three effector proteins, SseF, SseG, and SlrP, that have never before been visualized over time during infection of live cells...
June 9, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28537707/the-tyrosine-kinase-inhibitor-gefitinib-restricts-mycobacterium-tuberculosis-growth-through-increased-lysosomal-biogenesis-and-modulation-of-cytokine-signaling
#6
Kimberly M Sogi, Katie A Lien, Jeffrey R Johnson, Nevan J Krogan, Sarah A Stanley
Host-directed therapeutics have the potential to combat the global tuberculosis pandemic. We previously identified gefitinib, an inhibitor of EGFR, as a potential host-targeted therapeutic effective against Mycobacterium tuberculosis infection of macrophages and mice. Here we examine the functional consequences of gefitinib treatment on M. tuberculosis infected macrophages. Using phosphoproteomic and transcriptional profiling, we identify two mechanisms by which gefitinib influences macrophage responses to infection to affect cytokine responses and limit replication of M...
June 5, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28570820/human-milk-oligosaccharides-exhibit-antimicrobial-and-anti-biofilm-properties-against-group-b-streptococcus
#7
Dorothy L Ackerman, Ryan S Doster, Jörn-Hendrik Weitkamp, David Aronoff, Jennifer A Gaddy, Steven D Townsend
Streptococcus agalactiae (Group B Streptococcus, GBS) is a Gram-positive bacterial pathogen that causes invasive infections of both children and adults. During pregnancy, GBS is a significant cause of infection of the fetal membranes (chorioamnionitis), which can lead to intra-amniotic infection, preterm birth, stillbirth, and neonatal sepsis. Recently, breastfeeding has been thought to represent a potential mode of GBS transmission from mother to newborn, which might increase the risk for late-onset sepsis...
June 1, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28505405/structural-basis-for-xenosiderophore-utilization-by-the-human-pathogen-staphylococcus-aureus
#8
Nathaniel P Endicott, Eries Lee, Timothy A Wencewicz
Staphylococcus aureus produces a cocktail of metallophores (staphylopine, staphyloferrin A, and staphyloferrin B) to scavenge transition metals during infection of a host. In addition, S. aureus displays the extracellular surface lipoproteins FhuD1 and FhuD2 along with the ABC transporter complex FhuCBG to facilitate the use of hydroxamate xenosiderophores such as desferrioxamine B (DFOB) for iron acquisition. DFOB is used as a chelation therapy to treat human iron overload diseases and has been linked to an increased risk of S...
May 30, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28548487/the-challenge-of-overcoming-antibiotic-resistance-an-adjuvant-approach
#9
Roberta J Melander, Christian Melander
Antibiotic resistance is one of the greatest current threats to human health, and without significant action we face the chilling prospect of a world without effective antibiotics. Although continued effort toward the development of new antibiotics, particularly those with novel mechanisms of action, remains crucial, this alone probably will not be enough to prevail, and it is imperative that additional approaches are also explored. One such approach is the identification of adjuvants that augment the activity of current antibiotics...
May 26, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28475832/a-phenotypic-based-target-screening-approach-delivers-new-antitubercular-ctp-synthetase-inhibitors
#10
Marta Esposito, Sára Szadocka, Giulia Degiacomi, Beatrice S Orena, Giorgia Mori, Valentina Piano, Francesca Boldrin, Júlia Zemanová, Stanislav Huszár, David Barros, Sean Ekins, Joel Lelièvre, Riccardo Manganelli, Andrea Mattevi, Maria Rosalia Pasca, Giovanna Riccardi, Lluis Ballell, Katarína Mikušová, Laurent R Chiarelli
Despite its great potential, the target-based approach has been mostly unsuccessful in tuberculosis drug discovery, while whole cell phenotypic screening has delivered several active compounds. However, for many of these hits, the cellular target has not yet been identified, thus preventing further target-based optimization of the compounds. In this context, the newly validated drug target CTP synthetase PyrG was exploited to assess a target-based approach of already known, but untargeted, antimycobacterial compounds...
May 11, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28448118/diamide-inhibitors-of-the-bacillus-subtilis-n-acetylglucosaminidase-lytg-that-exhibit-antibacterial-activity
#11
Saman Nayyab, Mary O'Connor, Jennifer Brewster, James Gravier, Mitchell Jamieson, Ethan Magno, Ryan D Miller, Drew Phelan, Keyana Roohani, Paul Williard, Amit Basu, Christopher W Reid
N-Acetylglucosaminidases (GlcNAcases) play an important role in the remodeling and recycling of bacterial peptidoglycan by degrading the polysaccharide backbone. Genetic deletions of autolysins can impair cell division and growth, suggesting an opportunity for using small molecule autolysin inhibitors both as tools for studying the chemical biology of autolysins and also as antibacterial agents. We report here the synthesis and evaluation of a panel of diamides that inhibit the growth of Bacillus subtilis. Two compounds, fgkc (21) and fgka (5), were found to be potent inhibitors (MIC 3...
May 8, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28437604/antiplasmodial-mode-of-action-of-pantothenamides-pantothenate-kinase-serves-as-a-metabolic-activator-not-as-a-target
#12
Marianne de Villiers, Christina Spry, Cristiano J Macuamule, Leanne Barnard, Gordon Wells, Kevin J Saliba, Erick Strauss
N-Substituted pantothenamides (PanAms) are pantothenate analogues with up to nanomolar potency against blood-stage Plasmodium falciparum (the most virulent species responsible for malaria). Although these compounds are known to target coenzyme A (CoA) biosynthesis and/or utilization, their exact mode of action (MoA) is still unknown. Importantly, PanAms that retain the natural β-alanine moiety are more potent than other variants, consistent with the involvement of processes that are selective for pantothenate (the precursor of CoA) or its derivatives...
May 4, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28440625/antischistosomal-activity-of-pyrido-1-2-a-benzimidazole-derivatives-and-correlation-with-inhibition-of-%C3%AE-hematin-formation
#13
John Okombo, Kawaljit Singh, Godfrey Mayoka, Ferdinand Ndubi, Linley Barnard, Peter M Njogu, Mathew Njoroge, Liezl Gibhard, Christel Brunschwig, Mireille Vargas, Jennifer Keiser, Timothy J Egan, Kelly Chibale
The extensive use of praziquantel against schistosomiasis raises concerns about drug resistance. New therapeutic alternatives targeting critical pathways within the parasite are therefore urgently needed. Hemozoin formation in Schistosoma presents one such target. We assessed the in vitro antischistosomal activity of pyrido[1,2-a]benzimidazoles (PBIs) and investigated correlations with their ability to inhibit β-hematin formation. We further evaluated the in vivo efficacy of representative compounds in experimental mice and conducted pharmacokinetic analysis on the most potent...
May 3, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28434229/cell-cycle-dependent-kinase-cdk9-is-a-postexposure-drug-target-against-human-adenoviruses
#14
Vibhu Prasad, Maarit Suomalainen, Silvio Hemmi, Urs F Greber
Human adenoviruses (HAdVs) infect respiratory, gastrointestinal, and urinary tracts and give rise to eye infections and epidemic keratoconjunctivitis (EKC). They persist in lymphoid tissue and cause morbidity and mortality in immunocompromised people. Treatments with significant postexposure efficacy are not available. Here, we report that inhibition of the cell cycle-dependent kinase 9 (Cdk9) by RNA interference, or the compound flavopiridol, blocked infections with HAdV-C2/5, EKC-causing HAdV-D8/37, and progeny formation in human corneal epithelial and cancer cells...
April 27, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28350440/identification-of-trypanosoma-brucei-adometdc-inhibitors-using-a-high-throughput-mass-spectrometry-based-assay
#15
Oleg A Volkov, Casey C Cosner, Anthony J Brockway, Martin Kramer, Michael Booker, Shihua Zhong, Ariel Ketcherside, Shuguang Wei, Jamie Longgood, Melissa McCoy, Thomas E Richardson, Stephen A Wring, Michael Peel, Jeffrey D Klinger, Bruce A Posner, Jef K De Brabander, Margaret A Phillips
Human African trypanosomiasis (HAT) is a fatal infectious disease caused by the eukaryotic pathogen Trypanosoma brucei (Tb). Available treatments are difficult to administer and have significant safety issues. S-Adenosylmethionine decarboxylase (AdoMetDC) is an essential enzyme in the parasite polyamine biosynthetic pathway. Previous attempts to develop TbAdoMetDC inhibitors into anti-HAT therapies failed due to poor brain exposure. Here, we describe a large screening campaign of two small-molecule libraries (∼400,000 compounds) employing a new high-throughput (∼7 s per sample) mass spectrometry-based assay for AdoMetDC activity...
April 7, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28238256/discovery-of-a-novel-nitric-oxide-binding-protein-and-nitric-oxide-responsive-signaling-pathway-in-pseudomonas-aeruginosa
#16
Sajjad Hossain, Elizabeth M Boon
Nitric oxide (NO) is a radical diatomic gas molecule that, at low concentrations, plays important signaling roles in both eukaryotes and bacteria. In recent years, it has become evident that bacteria respond to low levels of NO in order to modulate their group behavior. Many bacteria respond via NO ligation to a well-established NO sensor called H-NOX (heme-nitric oxide/oxygen binding domain). Many others, such as Pseudomonas aeruginosa, lack an annotated hnoX gene in their genome yet are able to respond to low levels of NO to disperse their biofilms...
June 9, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28494592/acs-infectious-diseases-special-issue-focused-on-drug-discovery-for-global-health
#17
Courtney C Aldrich, Felix Calderón
No abstract text is available yet for this article.
May 12, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28388095/biomimetic-bacterial-identification-platform-based-on-thermal-wave-transport-analysis-twta-through-surface-imprinted-polymers
#18
Erik Steen Redeker, Kasper Eersels, Onno Akkermans, Jeroen Royakkers, Simba Dyson, Kunya Nurekeyeva, Beniamino Ferrando, Peter Cornelis, Marloes Peeters, Patrick Wagner, Hanne Diliën, Bart van Grinsven, Thomas Jan Cleij
This paper introduces a novel bacterial identification assay based on thermal wave analysis through surface-imprinted polymers (SIPs). Aluminum chips are coated with SIPs, serving as synthetic cell receptors that have been combined previously with the heat-transfer method (HTM) for the selective detection of bacteria. In this work, the concept of bacterial identification is extended toward the detection of nine different bacterial species. In addition, a novel sensing approach, thermal wave transport analysis (TWTA), is introduced, which analyzes the propagation of a thermal wave through a functional interface...
May 12, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28343384/n6-n6-and-o4-modifications-to-neomycin-affect-ribosomal-selectivity-without-compromising-antibacterial-activity
#19
Girish C Sati, Dimitri Shcherbakov, Sven N Hobbie, Andrea Vasella, Erik C Böttger, David Crich
The synthesis of a series of neomycin derivatives carrying the 2-hydroxyethyl substituent on N6' and/or N6‴ both alone and in combination with a 4'-O-ethyl group is described. By means of cell-free translation assays with wild-type bacterial ribosomes and their hybrids with eukaryotic decoding A sites, we investigate how individual substituents and their combinations affect activity and selectivity at the target level. In principle, and as shown by cell-free translation assays, modifications of the N6' and N6‴ positions allow enhancement of target selectivity without compromising antibacterial activity...
May 12, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28301927/molecular-mechanism-underlying-the-action-of-influenza-a-virus-fusion-inhibitor-mbx2546
#20
Arnab Basu, Gloria Komazin-Meredith, Courtney McCarthy, Aleksandar Antanasijevic, Steven C Cardinale, Rama K Mishra, Dale L Barnard, Michael Caffrey, Lijun Rong, Terry L Bowlin
Influenza A virus envelop protein hemagglutinin (HA) plays important roles in viral entry. We previously have reported that MBX2546, a novel influenza A virus inhibitor, binds to HA and inhibits HA-mediated membrane fusion. In this report, we show that (i) both binding and stabilization of HA by MBX2546 are required for the inhibition of viral infection and (ii) the binding of HA by MBX2546 represses the low-pH-induced conformational change in the HA, which is a prerequisite for membrane fusion. Mutations in MBX2546-resistant influenza A/PR/8/34 (H1N1) viruses are mapped in the HA stem region near the amino terminus of HA2...
May 12, 2017: ACS Infectious Diseases
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