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ACS Infectious Diseases

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https://www.readbyqxmd.com/read/28537707/the-tyrosine-kinase-inhibitor-gefitinib-restricts-mycobacterium-tuberculosis-growth-through-increased-lysosomal-biogenesis-and-modulation-of-cytokine-signaling
#1
Kimberly M Sogi, Katie A Lien, Jeffrey Johnson, Nevan J Krogan, Sarah 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 M. 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 impact cytokine responses and limit replication of M...
May 24, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28505405/structural-basis-for-xenosiderophore-utilization-by-the-human-pathogen-staphylococcus-aureus
#2
Nathaniel P Endicott, Eries Lee, Timothy Adam 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 15, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28475832/a-phenotypic-based-target-screening-approach-delivers-new-antitubercular-ctp-synthetase-inhibitors
#3
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
#4
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
#5
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
#6
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/the-cell-cycle-dependent-kinase-cdk9-is-a-post-exposure-drug-target-against-human-adenoviruses
#7
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 post-exposure 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 24, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28350440/identification-of-trypanosoma-brucei-adometdc-inhibitors-using-a-high-throughput-mass-spectrometry-based-assay
#8
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/28301927/molecular-mechanism-underlying-the-action-of-influenza-a-virus-fusion-inhibitor-mbx2546
#9
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...
April 3, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28264560/overcoming-an-extremely-drug-resistant-xdr-pathogen-avibactam-restores-susceptibility-to-ceftazidime-for-burkholderia-cepacia-complex-isolates-from-cystic-fibrosis-patients
#10
Krisztina M Papp-Wallace, Scott A Becka, Elise T Zeiser, Nozomi Ohuchi, Maria F Mojica, Julian A Gatta, Monica Falleni, Delfina Tosi, Elisa Borghi, Marisa L Winkler, Brigid M Wilson, John J LiPuma, Michiyoshi Nukaga, Robert A Bonomo
Burkholderia multivorans is a significant health threat to persons with cystic fibrosis (CF). Infections are difficult to treat as this pathogen is inherently resistant to multiple antibiotics. Susceptibility testing of isolates obtained from CF respiratory cultures revealed that single agents selected from different antibiotic classes were unable to inhibit growth. However, all isolates were found to be susceptible to ceftazidime when combined with the novel non-β-lactam β-lactamase inhibitor, avibactam (all minimum inhibitor concentrations (MICs) were ≤8 mg/L of ceftazidime and 4 mg/L of avibactam)...
March 30, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28350438/an-acyl-linked-dimer-of-daptomycin-is-strongly-inhibited-by-the-bacterial-cell-wall
#11
Robert M Taylor, Bradley Scott, Scott Taylor, Michael Palmer
The lipopeptide antibiotic daptomycin is active against Gram-positive pathogens. It permeabilizes bacterial cell membranes, which involves the formation of membrane-associated oligomers. We here studied a dimer of daptomycin whose two subunits were linked through a bivalent aliphatic acyl chain. Unexpectedly, the dimer had very low activity on vegetative Staphylococcus aureus and Bacillus subtilis cells. However, activity resembled that of monomeric daptomycin on liposomes and on B. subtilis L-forms. These findings underscore the importance of the bacterial cell wall in daptomycin resistance...
March 28, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28276676/a-screen-for-protein-protein-interactions-in-live-mycobacteria-reveals-a-functional-link-between-the-virulence-associated-lipid-transporter-lprg-and-the-mycolyltransferase-antigen-85a
#12
Megan H Touchette, Erik R Van Vlack, Lu Bai, Jia Kim, Armand B Cognetta, Mary L Previti, Keriann M Backus, Dwight W Martin, Benjamin F Cravatt, Jessica C Seeliger
Outer membrane lipids in pathogenic mycobacteria are important for virulence and survival. Although the biosynthesis of these lipids has been extensively studied, mechanisms responsible for their assembly in the outer membrane are not understood. In the study of Gram-negative outer membrane assembly, protein-protein interactions define transport mechanisms, but analogous interactions have not been explored in mycobacteria. Here we identified interactions with the lipid transport protein LprG. Using site-specific photo-cross-linking in live mycobacteria, we mapped three major interaction interfaces within LprG...
March 21, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28271875/in-vivo-selected-pyrazinoic-acid-resistant-mycobacterium-tuberculosis-strains-harbor-missense-mutations-in-the-aspartate-decarboxylase-pand-and-the-unfoldase-clpc1
#13
Pooja Gopal, Rokeya Tasneen, Michelle Yee, Jean-Philippe Lanoix, Jansy Sarathy, George Rasic, Liping Li, Véronique Dartois, Eric Nuermberger, Thomas Dick
Through mutant selection on agar containing pyrazinoic acid (POA), the bioactive form of the prodrug pyrazinamide (PZA), we recently showed that missense mutations in the aspartate decarboxylase PanD and the unfoldase ClpC1, and loss-of-function mutation of polyketide synthases Mas and PpsA-E involved in phthiocerol dimycocerosate synthesis, cause resistance to POA and PZA in Mycobacterium tuberculosis. Here we first asked whether these in vitro-selected POA/PZA-resistant mutants are attenuated in vivo, to potentially explain the lack of evidence of these mutations among PZA-resistant clinical isolates...
March 16, 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
#14
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...
March 16, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28264558/a-natural-lipotrisaccharide-and-its-derivatives-selectively-lyse-streptococcus-pneumoniae-via-interaction-with-cell-membrane
#15
Bo Liu, Xue Liu, Jing-Ren Zhang, Gang Liu
A natural lipotrisaccharide (NP000778, 1a), a new triglycosidic tri-O-substituted glycolipid isolated from the Morinda citrifolia plant, and its chemical derivatives were identified to be active against major Gram-positive pathogens, particularly Streptococcus pneumoniae. Additional evidence indicated that 1a and its synthetic derivatives exerted their bactericidal activities against S. pneumoniae by selectively targeting the bacterial membrane, leading to the rapid lysis of the pneumococci. Efficient synthesis of 1a and its derivatives was performed using an application of the intramolecular aglycon delivery (IAD) reaction to establish its structure-activity relationships (SARs)...
March 14, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28215073/identification-of-highly-specific-diversity-oriented-synthesis-derived-inhibitors-of-clostridium-difficile
#16
Jeremy R Duvall, Leanne Bedard, Adel M Naylor-Olsen, Abigail L Manson, Joshua A Bittker, Wenye Sun, Mark E Fitzgerald, Zhenmin He, Maurice D Lee, Jean-Charles Marie, Giovanni Muncipinto, Diane Rush, Deming Xu, Huisheng Xu, Mingliang Zhang, Ashlee M Earl, Michelle A Palmer, Michael A Foley, Joseph P Vacca, Christina A Scherer
In 2013, the Centers for Disease Control highlighted Clostridium difficile as an urgent threat for antibiotic-resistant infections, in part due to the emergence of highly virulent fluoroquinolone-resistant strains. Limited therapeutic options currently exist, many of which result in disease relapse. We sought to identify molecules specifically targeting C. difficile in high-throughput screens of our diversity-oriented synthesis compound collection. We identified two scaffolds with apparently novel mechanisms of action that selectively target C...
March 7, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28238255/linear-multiepitope-glyco-peptides-for-type-specific-serology-of-herpes-simplex-virus-hsv-infections
#17
Christian Risinger, Kasper K Sørensen, Knud J Jensen, Sigvard Olofsson, Tomas Bergström, Ola Blixt
Detection of type-specific antibodies is an important and essential part of accurate diagnosis, even in silent carriers of herpes simplex virus (HSV)-1 (oral) and HSV-2 (genital) infections. Serologic assays that identify HSV-1 and HSV-2 type-specific antibodies have been commercially available for more than a decade but often face problems related to cross-reactivity and similar issues. Attempts to identify type-specific peptide epitopes for use in serology for both HSV-1 and HSV-2 have been limited. We recently demonstrated epitope mapping of envelope glycoprotein G2 and identified a type-specific glycopeptide epitope that broadly recognized HSV-2 infected individuals...
March 6, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28244723/the-ecstasy-and-agony-of-assay-interference-compounds
#18
Courtney Aldrich, Carolyn Bertozzi, Gunda I Georg, Laura Kiessling, Craig Lindsley, Dennis Liotta, Kenneth M Merz, Alanna Schepartz, Shaomeng Wang
No abstract text is available yet for this article.
February 28, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28494592/acs-infectious-diseases-special-issue-focused-on-drug-discovery-for-global-health
#19
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
#20
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
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