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ACS Infectious Diseases

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https://www.readbyqxmd.com/read/28301927/molecular-mechanism-underlying-the-action-of-the-influenza-a-virus-fusion-inhibitor-mbx2546
#1
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 is required for inhibition of viral infection, and (ii) binding of HA by MBX2546 represses the low-pH-induced conformational change of 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...
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
#2
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
#3
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/28238268/aryl-alkyl-lysines-membrane-active-fungicides-that-act-against-biofilms-of-candida-albicans
#4
Chandradhish Ghosh, Vikas Yadav, Waleed Younis, Haroon Mohammad, Youssef A Hegazy, Mohamed N Seleem, Kaustuv Sanyal, Jayanta Haldar
Mortality due to pathogenic fungi has been exacerbated by the rapid development of resistance to frontline antifungal drugs. Fungicidal compounds with novel mechanisms of action are urgently needed. Aryl-alkyl-lysines, which are membrane-active small molecules, were earlier shown to be broad-spectrum antibacterial agents with potency in vitro and in vivo. Herein, we report the antifungal properties of aryl-alkyl-lysines. After identifying the most active compound (NCK-10), we tested its activity against a panel of clinically relevant pathogenic fungi and examined NCK-10's effect against immature and mature biofilms of Candida albicans...
March 14, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28285521/exploring-covalent-allosteric-inhibition-of-antigen-85c-from-mycobacterium-tuberculosis-by-ebselen-derivatives
#5
Christopher M Goins, Steven J Dajnowicz, Sandeep Thanna, Steven J Sucheck, Jerry Matthew Parks, Donald R Ronning
Previous studies identified ebselen as a potent in vitro and in vivo inhibitor of the Mycobacterium tuberculosis (Mtb) antigen 85 (Ag85) complex, comprising three homologous enzymes required for the biosynthesis of the mycobacterial cell wall. In this study, the Mtb Ag85C enzyme was co-crystallized with azido and adamantyl ebselen derivatives, resulting in two crystallographic structures of 2.01 and 1.30 Å resolution, respectively. Both structures displayed the anticipated covalent modification of the solvent accessible, non-catalytic Cys209 residue forming a selenenylsulfide bond...
March 13, 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
#6
Megan H Touchette, Erik Van Vlack, Lu Bai, Jia Kim, Armand B Cognetta, Mary Lou 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. While 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 photocrosslinking in live mycobacteria, we mapped three major interaction interfaces within LprG...
March 9, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28271875/in-vivo-selected-pyrazinoic-acid-resistant-m-tuberculosis-strains-harbor-missense-mutations-in-the-aspartate-decarboxylase-pand-and-the-unfoldase-clpc1
#7
Pooja Gopal, Rokeya Tasneen, Michelle Yee, Jean-Philippe Lanoix, Jansy Passiflora Sarathy, George Rasic, Liping Li, Veronique Dartois, E 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 8, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28215073/identification-of-highly-specific-diversity-oriented-synthesis-derived-inhibitors-of-clostridium-difficile
#8
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/28264560/overcoming-an-extreme-drug-resistant-xdr-pathogen-avibactam-restores-susceptibility-to-ceftazidime-for-burkholderia-cepacia-complex-isolates-from-cystic-fibrosis-patients
#9
Krisztina M Papp-Wallace, Scott A Becka, Elise T Zeiser, Nozumi 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 6, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28238255/linear-multiepitope-glyco-peptides-for-type-specific-serology-of-herpes-simplex-virus-hsv-infections
#10
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
#11
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/28207234/potassium-iodide-potentiates-broad-spectrum-antimicrobial-photodynamic-inactivation-using-photofrin
#12
Liyi Huang, Grzegorz Szewczyk, Tadeusz Sarna, Michael R Hamblin
It is known that noncationic porphyrins such as Photofrin (PF) are effective in mediating antimicrobial photodynamic inactivation (aPDI) of Gram-positive bacteria or fungi. However, the aPDI activity of PF against Gram-negative bacteria is accepted to be extremely low. Here we report that the nontoxic inorganic salt potassium iodide (KI) at a concentration of 100 mM when added to microbial cells (10(8)/mL) + PF (10 μM hematoporphyrin equivalent) + 415 nm light (10 J/cm(2)) can eradicate (>6 log killing) five different Gram-negative species (Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Proteus mirabilis, and Acinetobacter baumannii), whereas no killing was obtained without KI...
February 23, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28195698/structure-based-targeting-of-orthologous-pathogen-proteins-accelerates-antiparasitic-drug-discovery
#13
Vitul Jain, Arvind Sharma, Gajinder Singh, Manickam Yogavel, Amit Sharma
Parasitic diseases caused by eukaryotic pathogens impose significant health and economic burden worldwide. The level of research funding available for many parasitic diseases is insufficient in relation to their adverse social and economic impact. In this article, we discuss that extant 3D structural data on protein-inhibitor complexes can be harnessed to accelerate drug discovery against many related pathogens. Assessment of sequence conservation within drug/inhibitor-binding residues in enzyme-inhibitor complexes can be leveraged to predict and validate both new lead compounds and their molecular targets in multiple parasitic diseases...
February 23, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28118541/nonwoven-polymer-nanofiber-coatings-that-inhibit-quorum-sensing-in-staphylococcus-aureus-toward-new-nonbactericidal-approaches-to-infection-control
#14
Michael J Kratochvil, Tian Yang, Helen E Blackwell, David M Lynn
We report the fabrication and biological evaluation of nonwoven polymer nanofiber coatings that inhibit quorum sensing (QS) and virulence in the human pathogen Staphylococcus aureus. Our results demonstrate that macrocyclic peptide 1, a potent and synthetic nonbactericidal quorum sensing inhibitor (QSI) in S. aureus, can be loaded into degradable polymer nanofibers by electrospinning and that this approach can deposit QSI-loaded nanofiber coatings onto model nonwoven mesh substrates. The QSI was released over ∼3 weeks when these materials were incubated in physiological buffer, retained its biological activity, and strongly inhibited agr-based QS in a GFP reporter strain of S...
February 20, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28192916/combating-enhanced-intracellular-survival-eis-mediated-kanamycin-resistance-of-mycobacterium-tuberculosis-by-novel-pyrrolo-1-5-a-pyrazine-based-eis-inhibitors
#15
Atefeh Garzan, Melisa J Willby, Huy X Ngo, Chathurada S Gajadeera, Keith D Green, Selina Y L Holbrook, Caixia Hou, James E Posey, Oleg V Tsodikov, Sylvie Garneau-Tsodikova
Tuberculosis (TB) remains one of the leading causes of mortality worldwide. Hence, the identification of highly effective antitubercular drugs with novel modes of action is crucial. In this paper, we report the discovery and development of pyrrolo[1,5-a]pyrazine-based analogues as highly potent inhibitors of the Mycobacterium tuberculosis (Mtb) acetyltransferase enhanced intracellular survival (Eis), whose up-regulation causes clinically observed resistance to the aminoglycoside (AG) antibiotic kanamycin A (KAN)...
February 17, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28103015/antimicrobial-activity-ame-resistance-and-a-site-binding-studies-of-anthraquinone-neomycin-conjugates
#16
Natalya N Degtyareva, Changjun Gong, Sandra Story, Nathanael S Levinson, Adegboyega K Oyelere, Keith D Green, Sylvie Garneau-Tsodikova, Dev P Arya
The antibacterial effects of aminoglycosides are based on their association with the A-site of bacterial rRNA and interference with the translational process in the bacterial cell, causing cell death. The clinical use of aminoglycosides is complicated by resistance and side effects, some of which arise from their interactions with the human mitochondrial 12S rRNA and its deafness-associated mutations, C1494U and A1555G. We report a rapid assay that allows screening of aminoglycoside compounds to these classes of rRNAs...
February 17, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28142234/plasma-protein-binding-structure-activity-relationships-related-to-the-n-terminus-of-daptomycin
#17
Elena K Schneider, Johnny X Huang, Vincenzo Carbone, Meiling Han, Yan Zhu, Sue Nang, Keith K Khoo, Johnson Mak, Matthew A Cooper, Jian Li, Tony Velkov
Daptomycin is a lipopeptide antibiotic that is highly bound to plasma proteins. To date, the plasma components and structure-activity relationships responsible for the plasma protein binding profile of daptomycin remain uncharacterized. In the present study we have employed a surface plasmon resonance assay together with molecular docking techniques to investigate the plasma protein binding structure-activity relationships related to the N-terminal fatty acyl of daptomycin. Three compounds were investigated: (1) native daptomycin, which displays an N-terminal n-decanoyl fatty acid side chain, and two analogues with modifications to the N-terminal fatty acyl chain; (2) des-acyl daptomycin; and (3) acetyl-daptomycin...
February 10, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28155275/truncated-autoinducing-peptide-conjugates-selectively-recognize-and-kill-staphylococcus-aureus
#18
Kyoji Tsuchikama, Yasuhiro Shimamoto, Yasuaki Anami
The accessory gene regulator (agr) of Staphylococcus aureus coordinates various pathogenic events and is recognized as a promising therapeutic target for virulence control. S. aureus utilizes autoinducing peptides (AIPs), cyclic-peptide signaling molecules, to mediate the agr system. Despite the high potency of synthetic AIP analogues in agr inhibition, the potential of AIP molecules as a delivery vehicle for antibacterial agents remains unexplored. Herein, we report that truncated AIP scaffolds can be fused with fluorophore and cytotoxic photosensitizer molecules without compromising their high agr inhibitory activity, binding affinity to the receptor AgrC, or cell specificity...
February 6, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28157293/a-whole-cell-based-assay-to-evaluate-structure-permeation-relationships-for-carbapenem-passage-through-the-pseudomonas-aeruginosa-porin-oprd
#19
Ramkumar Iyer, Mark A Sylvester, Camilo Velez-Vega, Ruben Tommasi, Thomas F Durand-Reville, Alita A Miller
The global emergence of antibiotic resistance, especially in Gram-negative bacteria, is an urgent threat to public health. Discovery of novel classes of antibiotics with activity against these pathogens has been impeded by a fundamental lack of understanding of the molecular drivers underlying small molecule uptake. Although it is well-known that outer membrane porins represent the main route of entry for small, hydrophilic molecules across the Gram-negative cell envelope, the structure-permeation relationship for porin passage has yet to be defined...
February 3, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28075113/pseudomonas-aeruginosa-lasr%C3%A2-dna-binding-is-directly-inhibited-by-quorum-sensing-antagonists
#20
Emma G Suneby, Leslie R Herndon, Tanya L Schneider
Inhibition of quorum sensing in Pseudomonas aeruginosa is of interest as a possible antivirulence strategy for this pathogenic bacterium. The LasR regulator protein is important in coordinating gene expression in response to quorum sensing signaling molecules. One predominant strategy for LasR inhibition is the development of small-molecule antagonists that mimic the native autoinducer, though the mechanism by which they inactivate LasR is not known. This work reveals that multiple antagonists function by binding to and stabilizing LasR in a conformation that renders it unable to bind DNA...
January 11, 2017: ACS Infectious Diseases
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