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ACS Infectious Diseases

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https://www.readbyqxmd.com/read/28812869/entry-inhibitors-a-perspective-for-prevention-of-hepatitis-c-virus-infection-in-organ-transplantation
#1
Che C Colpitts, Raymond T Chung, Thomas F Baumert
Entry inhibitors are emerging as an attractive class of therapeutics for hepatitis C virus (HCV) infection. Entry inhibitors target either virion-associated factors or cellular factors necessary for infection. By blocking entry into cells, entry inhibitors prevent both the establishment of persistent reservoirs and the emergence of resistant variants during viral replication. Furthermore, entry inhibitors protect naïve cells from virus-induced alterations. Combining entry inhibitors with direct-acting antivirals (DAAs) may therefore improve treatment outcomes, particularly in the context of organ transplantation...
August 16, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28786661/catabolism-of-the-cholesterol-side-chain-in-mycobacterium-tuberculosis-is-controlled-by-a-redox-sensitive-thiol-switch
#2
Rui Lu, Christin M Schaefer, Natasha M Nesbitt, Jochen Kuper, Caroline Kisker, Nicole S Sampson
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is a highly successful human pathogen and has infected approximately one-third of the world's population. Multiple drug resistant (MDR) and extensively drug resistant (XDR) TB strains and coinfection with HIV have increased the challenges of successfully treating this disease pandemic. The metabolism of host cholesterol by Mtb is an important factor for both its virulence and pathogenesis. In Mtb, the cholesterol side chain is degraded through multiple cycles of β-oxidation and FadA5 (Rv3546) catalyzes side chain thiolysis in the first two cycles...
August 16, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28756664/structural-and-functional-survey-of-environmental-aminoglycoside-acetyltransferases-reveals-functionality-of-resistance-enzymes
#3
Zhiyu Xu, Peter J Stogios, Andrew T Quaile, Kevin J Forsberg, Sanket Patel, Tatiana Skarina, Scott Houliston, Cheryl Arrowsmith, Gautam Dantas, Alexei Savchenko
Aminoglycoside N-acetyltransferases (AACs) confer resistance against the clinical use of aminoglycoside antibiotics. The origin of AACs can be traced to environmental microbial species representing a vast reservoir for new and emerging resistance enzymes, which are currently undercharacterized. Here, we performed detailed structural characterization and functional analyses of four metagenomic AAC (meta-AACs) enzymes recently identified in a survey of agricultural and grassland soil microbiomes ( Forsberg et al...
August 16, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28810737/identification-of-the-colicin-v-bacteriocin-gene-cluster-by-functional-screening-of-a-human-microbiome-metagenomic-library
#4
Louis Cohen, Sun Han, Yun-Han Huang, Sean F Brady
The forces that shape human microbial ecology are complex. It is likely, that human microbiota, similarly to other microbiomes, use antibiotics as one way to establish an ecological niche. In this study, we use functional metagenomics to identify human microbial gene clusters that encode for antibiotic functions. Screening of a metagenomic library prepared from a healthy patient stool sample led to the identification of a family of clones with inserts that are 99% identical to a region of a virulence plasmid found in avian pathogenic Escherichia coli...
August 15, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28799332/attaching-the-nora-efflux-pump-inhibitor-inf55-to-methylene-blue-enhances-antimicrobial-photodynamic-inactivation-of-methicillin-resistant-staphylococcus-aureus-in-vitro-and-in-vivo
#5
Ardeshir Rineh, Naveen K Dolla, Anthony R Ball, Maria Magana, John B Bremner, Michael R Hamblin, George P Tegos, Michael J Kelso
Antimicrobial photodynamic inactivation (aPDI) uses photosensitizers (PSs) and harmless visible light to generate reactive oxygen species (ROS) and kill microbes. Multidrug efflux systems can moderate the phototoxic effects of PSs by expelling the compounds from cells. We hypothesized that increasing intracellular concentrations of PSs by inhibiting efflux with a covalently attached efflux pump inhibitor (EPI) would enhance bacterial cell phototoxicity and reduce exposure of neighbouring host cells to damaging ROS...
August 11, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28762275/ribosome-rescue-inhibitors-kill-actively-growing-and-nonreplicating-persister-mycobacterium-tuberculosis-cells
#6
John N Alumasa, Paolo S Manzanillo, Nicholas D Peterson, Tricia Lundrigan, Anthony D Baughn, Jeffery S Cox, Kenneth C Keiler
The emergence of Mycobacterium tuberculosis (MTB) strains that are resistant to most or all available antibiotics has created a severe problem for treating tuberculosis and has spurred a quest for new antibiotic targets. Here, we demonstrate that trans-translation is essential for growth of MTB and is a viable target for development of antituberculosis drugs. We also show that an inhibitor of trans-translation, KKL-35, is bactericidal against MTB under both aerobic and anoxic conditions. Biochemical experiments show that this compound targets helix 89 of the 23S rRNA...
August 7, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28770988/teixobactin-and-its-analogues-a-new-hope-in-antibiotic-discovery
#7
William D Fiers, Mark Craighead, Ishwar Singh
Increasing bacterial resistance against current antibiotics and lack of new molecules to combat bacterial resistance are key challenges to global health. There is, therefore, a continuing need to develop new antibiotics. Teixobactin, a cyclic undecapeptide, displays excellent antibacterial activities against a range of pathogenic bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA) and Mycobacterium tuberculosis. Interestingly, it operates by multiple modes of actions and is bactericidal toward S...
August 3, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28758395/hydrophilic-phage-mimicking-membrane-active-antimicrobials-reveal-nanostructure-dependent-activity-and-selectivity
#8
Yunjiang Jiang, Wan Zheng, Liangju Kuang, Hairong Ma, Hongjun Liang
The prevalent wisdom on developing membrane active antimicrobials (MAAs) is to seek a delicate, yet unquantified cationic-hydrophobic balance. Inspired by phages that use nanostructured protein devices to invade bacteria efficiently and selectively, we study here the antibiotic role of nanostructures by designing spherical and rod-like polymer molecular brushes (PMBs) that mimic the two basic structural motifs of bacteriophages. Three model PMBs with different well-defined geometries consisting of multiple identical copies of densely packed poly(4-vinyl-N-methylpyridine iodide) branches are synthesized by controlled/"living" polymerization, reminiscence of the viral structural motifs comprised of multiple copies of protein subunits...
July 31, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28686009/ferrocenyl-ruthenocenyl-and-benzyl-oxamniquine-derivatives-with-cross-species-activity-against-schistosoma-mansoni-and-schistosoma-haematobium
#9
Jeannine Hess, Gordana Panic, Malay Patra, Luciano Mastrobuoni, Bernhard Spingler, Saonli Roy, Jennifer Keiser, Gilles Gasser
Schistosomiasis is a parasitic disease that affects more than 250 million people annually, mostly children in poor, tropical, rural areas. Only one treatment (praziquantel) is available, putting control efforts at risk should resistance occur. In pursuit of treatment alternatives, we derivatized an old antischistosomal agent, oxamniquine (OXA). Four organometallic derivatives of OXA were synthesized and tested against Schistosoma mansoni in vitro and in vivo. Of these, a ferrocenyl derivative, 1, killed larval and adult worms 24 h postexposure in vitro, in contrast to OXA, which lacks in vitro activity against adult worms...
July 18, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28707874/designing-probes-for-immunodiagnostics-structural-insights-into-an-epitope-targeting-i-burkholderia-i-infections
#10
Riccardo Capelli, Elena Matterazzo, Marco Amabili, Claudio Peri, Alessandro Gori, Paola Gagni, Marcella Chiari, Ganjana Lertmemongkolchai, Marina Cretich, Martino Bolognesi, Giorgio Colombo, Louise Jane Gourlay
Structure-based epitope prediction drives the design of diagnostic peptidic probes to reveal specific antibodies elicited in response to infections. We previously identified a highly immunoreactive epitope from the peptidoglycan-associated lipoprotein (Pal) antigen from <i>Burkholderia pseudomallei</i>, which could also diagnose <i>Burkholderia cepacia</i> infections. Here, considering the high phylogenetic conservation within <i>Burkholderia</i> species, we ask whether cross-reactivity can be reciprocally displayed by the synthetic epitope from <i>B...
July 14, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28695731/investigating-the-interaction-of-octapeptin-a3-with-model-bacterial-membranes
#11
Mei-Ling Han, Hsin-Hui Shen, Karl A Hansford, Elena K Schneider, Sivashangarie Sivanesan, Kade D Roberts, Philip E Thompson, Anton P Le Brun, Yan Zhu, Marc-Antoine Sani, Frances Separovic, Mark A T Blaskovich, Mark A Baker, Samuel M Moskowitz, Matthew A Cooper, Jian Li, Tony Velkov
Octapeptins are cyclic lipopeptides with a broader spectrum of activity against fungi and polymyxin-resistant Gram-negative and Gram-positive bacteria. In the present study, we investigated the interaction of octapeptin A3 with asymmetric outer membrane models of Gram-negative pathogen Pseudomonas aeruginosa using neutron reflectometry, together with fluorimetric and calorimetry methods. For the first time, our neutron reflectometry results reveal that the interaction of octapeptin A3 with the Gram-negative outer membrane involves an initial transient polar interaction with the phospholipid and lipid A headgroups, followed by the penetration of the entire octapeptin molecule into the fatty acyl core of the outer membrane...
July 11, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28605587/allosteric-regulation-of-phosphatidylinositol-4-kinase-iii-beta-by-an-antipicornavirus-compound-mdl-860
#12
Minetaro Arita, Georgi Dobrikov, Gerhard Pürstinger, Angel S Galabov
MDL-860 is a broad-spectrum antipicornavirus 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 antipoliovirus 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 28, 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
#13
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/28570820/human-milk-oligosaccharides-exhibit-antimicrobial-and-antibiofilm-properties-against-group-b-streptococcus
#14
Dorothy L Ackerman, Ryan S Doster, Jörn-Hendrik Weitkamp, David M Aronoff, Jennifer A Gaddy, Steven D Townsend
Streptococcus agalactiae (Group B Streptococcus, GBS) is a Gram-positive bacterial pathogen that causes invasive infections in 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 13, 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
#15
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
#16
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/28548487/the-challenge-of-overcoming-antibiotic-resistance-an-adjuvant-approach
#17
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/28797168/nano-tools-pave-the-way-to-new-solutions-in-infectious-disease
#18
Paula T Hammond
No abstract text is available yet for this article.
August 11, 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
#19
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...
July 14, 2017: ACS Infectious Diseases
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
#20
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...
July 14, 2017: ACS Infectious Diseases
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