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ACS Infectious Diseases

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https://www.readbyqxmd.com/read/28118541/nonwoven-polymer-nanofiber-coatings-that-inhibit-quorum-sensing-in-staphylococcus-aureus-toward-new-nonbactericidal-approaches-to-infection-control
#1
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/28215073/identification-of-highly-specific-diversity-oriented-synthesis-derived-inhibitors-of-clostridium-difficile
#2
Jeremy R Duvall, Leanne Bedard, Adel M Naylor-Olsen, Abigail L Manson, Joshua A Bittker, Wenye Sun, Mark E Fitzgerald, Zhenmin He, Maurice Dupont 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...
February 19, 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
#3
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
#4
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/28207234/potassium-iodide-potentiates-broad-spectrum-antimicrobial-photodynamic-inactivation-using-photofrin
#5
Liyi Huang, Grzegorz Szewczyk, Tadeusz Sarna, Michael R Hamblin
It is known that non-cationic 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 non-toxic inorganic salt, potassium iodide (KI) at a concentration of 100mM when added to microbial cells (10(8)/mL) + PF (10µM hematoporphyrin equivalent) + 415nm light (10J/cm2) can eradicate (>6 logs killing) five different Gram-negative species (Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Proteus mirabilis, and Acinetobacter baumannii), while no killing was obtained without KI...
February 16, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28195698/structure-based-targeting-of-orthologous-pathogen-proteins-accelerates-anti-parasitic-drug-discovery
#6
Vitul Jain, Arvind Sharma, Gajinder Pal 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 impact. Here, we review the extant 3D structural data on protein-inhibitor complexes that 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 14, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28142234/plasma-protein-binding-structure-activity-relationships-related-to-the-n-terminus-of-daptomycin
#7
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/28152588/a-sensitive-in-vitro-high-throughput-screen-to-identify-pan-filoviral-replication-inhibitors-targeting-the-vp35-np-interface
#8
Gai Liu, Peter J Nash, Britney Johnson, Colette Pietzsch, Ma Xenia G Ilagan, Alexander Bukreyev, Christopher F Basler, Terry L Bowlin, Donald T Moir, Daisy W Leung, Gaya K Amarasinghe
The 2014 Ebola outbreak in West Africa, the largest outbreak on record, highlighted the need for novel approaches to therapeutics targeting Ebola virus (EBOV). Within the EBOV replication complex, the interaction between polymerase cofactor, viral protein 35 (VP35), and nucleoprotein (NP) is critical for viral RNA synthesis. We recently identified a peptide at the N-terminus of VP35 (termed NPBP) that is sufficient for interaction with NP and suppresses EBOV replication, suggesting that the NPBP binding pocket can serve as a potential drug target...
February 9, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28155275/truncated-autoinducing-peptide-conjugates-selectively-recognize-and-kill-staphylococcus-aureus
#9
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
#10
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/28135798/rational-design-of-single-chain-polymeric-nanoparticles-that-kill-planktonic-and-biofilm-bacteria
#11
Thuy-Khanh Nguyen, Shu Jie Lam, Kitty Ka Kit Ho, Naresh Kumar, Greg G Qiao, Suhelen Egan, Cyrille Boyer, Edgar H H Wong
Infections caused by multidrug-resistant bacteria are on the rise and as such, new antimicrobial agents are required to prevent the onset of a post-antibiotic era. In this study, we develop new antimicrobial compounds in the form of single-chain polymeric nanoparticles (SCPNs) that exhibit excellent antimicrobial activity against Gram-negative bacteria (e.g., Pseudomonas aeruginosa) at µM concentrations (e.g., 1.1 µM), and remarkably kill ≥ 99.99% of both planktonic cells and biofilm within an hour. Linear random copolymers, which comprise of oligoethylene glycol (OEG), hydrophobic and amine groups, undergo self-folding in aqueous due to intramolecular hydrophobic interactions to yield these SCPNs...
January 30, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28086019/hk2-recruitment-to-phospho-bad-prevents-its-degradation-promoting-warburg-glycolysis-by-theileria-transformed-leukocytes
#12
Malak Haidar, Anne Lombès, Frédéric Bouillaud, Eileen J Kennedy, Gordon Langsley
Theileria annulata infects bovine leukocytes, transforming them into invasive, cancer-like cells that cause the widespread disease called tropical theileriosis. We report that in Theileria-transformed leukocytes hexokinase-2 (HK2) binds to B cell lymphoma-2-associated death promoter (BAD) only when serine (S) 155 in BAD is phosphorylated. We show that HK2 recruitment to BAD is abolished by a cell-penetrating peptide that acts as a nonphosphorylatable BAD substrate that inhibits endogenous S155 phosphorylation, leading to complex dissociation and ubiquitination and degradation of HK2 by the proteasome...
January 24, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28110521/from-cells-to-mice-to-target-characterization-of-neu-1053-sb-443342-and-its-analogs-for-treatment-of-human-african-trypanosomiasis
#13
William G Devine, Rosario Díaz González, Gloria Ceballos-Perez, Domingo Isaac Rojas-Barros, Takashi Satoh, Westley Tear, Ranae M Ranade, Ximena Barros-Álvarez, Wim G J Hol, Frederick S Buckner, Miguel Navarro, Michael P Pollastri
Human African Trypanosomiasis is a neglected tropical disease that is lethal if left untreated. Existing therapeutics have limited efficacy and severe associated toxicities. 2-(2-(((3-((1H-Benzo[d]imidazol-2-yl)amino)propyl)amino)methyl)-4,6-dichloro-1H-indol-1-yl)ethan-1-ol (NEU-1053) has recently been identified from a high throughput screen of >42,000 compounds as a highly potent and fast acting trypanocidal agent capable of curing a blood stream infection of T. brucei in mice. We have designed a library of analogs to probe the SAR and improve the predicted CNS exposure of NEU-1053...
January 22, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28075113/pseudomonas-aeruginosa-lasr%C3%A2-dna-binding-is-directly-inhibited-by-quorum-sensing-antagonists
#14
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
https://www.readbyqxmd.com/read/27989113/optimization-and-synthesis-of-pyridazinone-derivatives-as-novel-inhibitors-of-hepatitis-b-virus-by-inducing-genome-free-capsid-formation
#15
Dong Lu, Feifei Liu, Weiqiang Xing, Xiankun Tong, Lang Wang, Yajuan Wang, Limin Zeng, Chunlan Feng, Li Yang, Jianping Zuo, Youhong Hu
The capsid of hepatitis B virus (HBV) plays a vital role in virus DNA replication. Targeting nucleocapsid function has been demonstrated as an effective approach for anti-HBV drug development. A high-throughput screening and mechanism study revealed the hit compound 4a as an HBV assembly effector (AEf), which could inhibit HBV replication by inducing the formation of HBV DNA-free capsids. The subsequent SAR study and drug-like optimization resulted in the discovery of the lead candidate 4r, with potent antiviral activity (IC50 = 0...
December 29, 2016: ACS Infectious Diseases
https://www.readbyqxmd.com/read/27957853/characterization-of-the-direct-interaction-between-hybrid-sensor-kinases-pa1611-and-rets-that-controls-biofilm-formation-and-the-type-iii-secretion-system-in-pseudomonas-aeruginosa
#16
Anjali Y Bhagirath, Sai P Pydi, Yanqi Li, Chen Lin, Weina Kong, Prashen Chelikani, Kangmin Duan
One of the leading causes of morbidity and mortality in cystic fibrosis (CF) patients is pulmonary infection with Pseudomonas aeruginosa, and the pathophysiology of pulmonary infection in CF is affected by the lifestyle of this micro-organism. RetS-GacS/A-RsmA is a key regulatory pathway in P. aeruginosa that determines the bacterium's lifestyle choice. Previously, we identified PA1611, a hybrid sensor kinase, as a new player in this pathway that interacts with RetS and influences biofilm formation and type III secretion system...
December 13, 2016: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28183186/introducing-a-new-associate-editor-for-acs-infectious-diseases
#17
Courtney C Aldrich
No abstract text is available yet for this article.
February 10, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28183185/rational-design-of-selective-and-bioactive-inhibitors-of-the-mycobacterium-tuberculosis-proteasome
#18
Kyle A Totaro, Dominik Barthelme, Peter T Simpson, Xiuju Jiang, Gang Lin, Carl F Nathan, Robert T Sauer, Jason K Sello
The 20S core particle of the proteasome in Mycobacterium tuberculosis (Mtb) is a promising, yet unconventional, drug target. This multimeric peptidase is not essential, yet degrades proteins that have become damaged and toxic via reactions with nitric oxide (and/or the associated reactive nitrogen intermediates) produced during the host immune response. Proteasome inhibitors could render Mtb susceptible to the immune system, but they would only be therapeutically viable if they do not inhibit the essential 20S counterpart in humans...
February 10, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28183184/a-small-covalent-allosteric-inhibitor-of-human-cytomegalovirus-dna-polymerase-subunit-interactions
#19
Han Chen, Molly Coseno, Scott B Ficarro, My Sam Mansueto, Gloria Komazin-Meredith, Sandrine Boissel, David J Filman, Jarrod A Marto, James M Hogle, Donald M Coen
Human cytomegalovirus DNA polymerase comprises a catalytic subunit, UL54, and an accessory subunit, UL44, the interaction of which may serve as a target for the development of new antiviral drugs. Using a high-throughput screen, we identified a small molecule, (5-((dimethylamino)methylene-3-(methylthio)-6,7-dihydrobenzo[c]thiophen-4(5H)-one), that selectively inhibits the interaction of UL44 with a UL54-derived peptide in a time-dependent manner, full-length UL54, and UL44-dependent long-chain DNA synthesis...
February 10, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28183183/in-this-issue
#20
Lorraine F Clark
No abstract text is available yet for this article.
February 10, 2017: ACS Infectious Diseases
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