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ACS Infectious Diseases

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https://www.readbyqxmd.com/read/29140081/the-human-milk-glycome-as-a-defense-against-infectious-diseases-rationale-challenges-and-opportunities
#1
Kelly M Craft, Steven D Townsend
Each year over 3 million people die from infectious diseases with most of these deaths being poor and young children who live in low- and middle-income countries. Infectious diseases emerge for a multitude of reasons. On the social front, reasons include a breakdown of public health standards, international travel, and immigration (for financial, civil, and social reasons). At the molecular level, the modern rise of infectious diseases is tied to the juxtaposition of drug-resistant pathogens and a lack of new antimicrobials...
November 15, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29134797/the-importance-of-collaboration-between-industry-academics-and-nonprofits-in-tropical-disease-drug-discovery
#2
Lori Ferrins, Michael P Pollastri
Collaborations between academic, industrial, and nonprofit companies can provide sufficient impetus to propel projects that have little economic return; such projects are prevalent in tropical disease drug discovery. In these collaborations, each partner contributes a unique set of skills and technical expertise which is advantageous to the project as a whole. Highly product-focused processes and specialized expertise sets dominate industry groups. When coupled with the strategic guidance from public-private partnerships and the academic tendency to work on high-risk projects with low financial rewards, a powerful combination results...
November 14, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29131575/halogenation-of-biotin-protein-ligase-inhibitors-improves-whole-cell-activity-against-staphylococcus-aureus
#3
Ashleigh S Paparella, Kwang J Lee, Andrew Hayes, Jiage Feng, Zikai Feng, Danielle Cini, Sonali Deshmukh, Grant William Booker, Matthew C J Wilce, Steven W Polyak, Andrew D Abell
We report the synthesis and evaluation of 5-halogenated-1,2,3-triazoles as inhibitors of biotin protein ligase from Staphylococcus aureus. The halogenated compounds exhibit significantly improved antibacterial activity over their non-halogenated counterparts. Importantly, the 5-fluoro-1,2,3-triazole compound 4c displays antibacterial activity against S. aureus ATCC49775 with a minimum inhibitory concentration (MIC) of 8 μg/mL.
November 13, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29094594/nonsteroidal-anti-inflammatory-drug-induced-leaky-gut-modeled-using-polarized-monolayers-of-primary-human-intestinal-epithelial-cells
#4
Aadra P Bhatt, Dulan B Gunasekara, Jennifer Speer, Mark I Reed, Alexis N Peña, Bentley R Midkiff, Scott T Magness, Scott J Bultman, Nancy L Allbritton, Matthew R Redinbo
The intestinal epithelium provides a critical barrier that separates the gut microbiota from host tissues. Nonsteroidal anti-inflammatory drugs (NSAIDs) are efficacious analgesics and antipyretics and are among the most frequently used drugs worldwide. In addition to gastric damage, NSAIDs are toxic to the intestinal epithelium, causing erosions, perforations, and longitudinal ulcers in the gut. Here, we use a unique in vitro human primary small intestinal cell monolayer system to pinpoint the intestinal consequences of NSAID treatment...
November 10, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29120606/management-of-respiratory-infections-with-use-of-procalcitonin-moving-toward-more-personalized-antibiotic-treatment-decisions
#5
Yannick Wirz, Angela Branche, Michel Wolff, Tobias Welte, Vandack Nobre, Konrad Reinhart, Ann R Falsey, Pierre Damas, Albertus Beishuizen, Rodrigo O Deliberato, Yahya Shehabi, Jens-Ulrik S Jensen, Beat Mueller, Philipp Schuetz
Due to overlap of clinical findings and low sensitivity of bacterial diagnostic tests, differentiation between bacterial and viral respiratory tract infections remains challenging, ultimately leading to antibiotic overuse in this population of patients. Addition of procalcitonin, a blood biomarker expressed by epithelial cells in response to bacterial infections, to the clinical assessment leads to a reduction in inappropriate antibiotic initiation. Procalcitonin also provides prognostic information about the resolution of illness, and significant decreases over time are a strong signal for the discontinuation of antibiotics...
November 9, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29091730/probing-the-interaction-of-aspergillomarasmine-a-with-metallo-%C3%AE-lactamases-ndm-1-vim-2-and-imp-7
#6
Alexander Bergstrom, Andrew Katko, Zach Adkins, Jessica Hill, Zishuo Cheng, Mia Burnett, Hao Yang, Mahesh Aitha, M Rachel Mehaffey, Jennifer S Brodbelt, Kamaleddin H M E Tehrani, Nathaniel I Martin, Robert A Bonomo, Richard C Page, David L Tierney, Walter Fast, Gerard D Wright, Michael W Crowder
Metallo-β-lactamases (MBLs) are a growing threat to the continued efficacy of β-lactam antibiotics. Recently, aspergillomarasmine A (AMA) was identified as an MBL inhibitor, but the mode of inhibition was not fully characterized. Equilibrium dialysis and metal analysis studies revealed that 2 equiv of AMA effectively removes 1 equiv of Zn(II) from MBLs NDM-1, VIM-2, and IMP-7 when the MBL is at micromolar concentrations. Conversely, (1)H NMR studies revealed that 2 equiv of AMA remove 2 equiv of Co(II) from Co(II)-substituted NDM-1, VIM-2, and IMP-7 when the MBL/AMA are at millimolar concentrations...
November 9, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29115136/kinetic-control-of-quorum-sensing-in-pseudomonas-aeruginosa-by-multidrug-efflux-pumps
#7
David Wolloscheck, Ganesh Krishnamoorthy, Jennifer Nguyen, Helen I Zgurskaya
Pseudomonas aeruginosa is an important human pathogen, the physiology and virulence of which are under the control of quorum sensing signals. These signals often have dual roles, functioning as toxins to some cells and as oxidative-stress protectors for their producer cells. Hence, their internal and external concentrations should be tightly controlled. In this study, we analyzed the interplay between the multidrug efflux transporters MexEF-OprN and MexG/HI-OpmD in quorum sensing of P. aeruginosa. We found that the two transporters have overlapping substrate specificities but different efficiencies...
November 8, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29072835/biological-studies-and-target-engagement-of-the-2-c-methyl-d-erythritol-4-phosphate-cytidylyltransferase-ispd-targeting-antimalarial-agent-1r-3s-mmv008138-and-analogs
#8
Maryam Ghavami, Emilio F Merino, Zhong-Ke Yao, Rubayet Elahi, Morgan E Simpson, Maria L Fernández-Murga, Joshua H Butler, Michael A Casasanta, Priscilla M Krai, Maxim M Totrov, Daniel J Slade, Paul R Carlier, Maria Belen Cassera
Malaria continues to be one of the deadliest diseases worldwide, and the emergence of drug resistance parasites is a constant threat. Plasmodium parasites utilize the methylerythritol phosphate (MEP) pathway to synthesize isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are essential for parasite growth. Previously, we and others identified that the Malaria Box compound MMV008138 targets the apicoplast and that parasite growth inhibition by this compound can be reversed by supplementation of IPP...
November 7, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29108416/chlorflavonin-targets-acetohydroxyacid-synthase-catalytic-subunit-ilvb1-for-synergistic-killing-of-mycobacterium-tuberculosis
#9
Nidja Rehberg, Herve Sergi Akone, Thomas R Ioerger, German Erlenkamp, Georgios Daletos, Holger Gohlke, Peter Proksch, Rainer Kalscheuer
The flavonoid natural compound chlorflavonin was isolated from the endophytic fungus Mucor irregularis, which was obtained from the Cameroonian medicinal plant Moringa stenopetala. Chlorflavonin exhibited strong growth inhibitory activity in vitro against Mycobacterium tuberculosis (MIC90 1.56 μM) while exhibiting no cytotoxicity towards the human cell lines MRC-5 and THP-1 up to concentrations of 100 µM. Mapping of resistance-mediating mutations employing whole-genome sequencing, chemical supplementation assays, molecular docking studies as well as enzymatic characterization revealed that chlorflavonin specifically inhibits the acetohydroxyacid synthase catalytic subunit IlvB1, causing combined auxotrophies to branched chain amino acids and to pantothenic acid...
November 6, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29058407/antifungal-phenothiazines-optimization-characterization-of-mechanism-and-modulation-of-neuroreceptor-activity
#10
Marhiah C Montoya, Louis DiDone, Richard F Heier, Marvin J Meyers, Damian J Krysan
New classes of antifungal drugs are an urgent unmet clinical need. One approach to the challenge of developing new antifungal drugs is to optimize the antifungal properties of currently used drugs with favorable pharmacologic properties, so-called drug or scaffold repurposing. New therapies for cryptococcal meningitis are particularly important given its worldwide burden of disease and limited therapeutic options. We report the first systematic structure-activity study of the anticryptococcal properties of the phenothiazines...
November 2, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29045123/polymyxin-b3-tobramycin-hybrids-with-pseudomonas-aeruginosa-selective-antibacterial-activity-and-strong-potentiation-of-rifampicin-minocycline-and-vancomycin
#11
Ronald Domalaon, Xuan Yang, Yinfeng Lyu, George G Zhanel, Frank Schweizer
There is an urgent need to develop novel antibacterial agents able to eradicate drug-resistant Gram-negative pathogens such as Pseudomonas aeruginosa. Antimicrobial hybrids have emerged as a promising strategy to combat bacterial resistance, as a stand-alone drug but also as an adjuvant in combination with existing antibiotics. Herein, we report for the first time the synthesis and biological evaluation of polymyxin-aminoglycoside heterodimers composed of polymyxin B3 covalently linked to tobramycin via an aliphatic hydrocarbon linker...
October 27, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29043768/infection-of-ipsc-lines-with-miscarriage-associated-coxsackievirus-and-measles-virus-and-teratogenic-rubella-virus-as-a-model-for-viral-impairment-of-early-human-embryogenesis
#12
Denise Hübner, Kristin Jahn, Sandra Pinkert, Janik Böhnke, Matthias Jung, Henry Fechner, Dan Rujescu, Uwe Gerd Liebert, Claudia Claus
Human induced pluripotent stem cell (iPSC) lines are a promising model for the early phase of human embryonic development. Here, their contribution to the still incompletely understood pathogenesis of congenital virus infections was evaluated. The infection of iPSC lines with miscarriage-associated coxsackievirus B3 (CVB3) and measles virus (MV) was compared to the efficient teratogen rubella virus (RV). While CVB3 and MV were found to be cytopathogenic on iPSC lines, RV replicated without impairment of iPSC colony morphology and integrity...
October 26, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29069544/exploiting-the-sensitivity-of-nutrient-transporter-deletion-strains-in-discovery-of-natural-product-antimetabolites
#13
Eric D Brown, Sebastian S Gehrke, Garima Kumar, Nicole A Yokubynas, Jean-Philippe Côté, Wenliang Wang, Shawn French, Craig R MacNair, Gerard D Wright
Actinomycete secondary metabolites are a renowned source of antibacterial chemical scaffolds. Herein, we present a target-specific approach that increases the detection of antimetabolites from natural sources by screening actinomycete-derived extracts against nutrient transporter deletion strains. Based on the growth rescue patterns of a collection of 22 E. coli auxotrophic deletion strains representative of the major nutrient biosynthetic pathways, we demonstrate that antimetabolite detection from actinomycete-derived extracts prepared using traditional extraction platforms is masked by nutrient supplementation...
October 25, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29048870/daptomycin-pore-formation-is-restricted-by-lipid-acyl-chain-composition
#14
Robert Taylor, David Beriashvili, Scott Taylor, Michael Palmer
Daptomycin is a calcium-dependent lipopeptide antibiotic that is used clinically against various Gram-positive pathogens. It acts on bacterial cell membranes, whose susceptibility varies with the content of phosphatidylglycerol (PG). Some studies have reported that daptomycin permeabilizes and depolarizes bacterial cell membranes, while others have found no evidence of membrane permeabilization and thus proposed different mechanisms of antibacterial action. Divergent observations have also been reported regarding the effect of daptomycin on model membranes, which were found to be permeabilized nonselectively, selectively for small cations, or not at all...
October 23, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29043783/marine-mammal-microbiota-yields-novel-antibiotic-with-potent-activity-against-clostridium-difficile
#15
Jessica L Ochoa, Laura M Sanchez, Byoung-Mo Koo, Jennifer S Doherty, Manohary Rajendram, Kerwyn Casey Huang, Carol A Gross, Roger G Linington
The recent explosion of research on the microbiota has highlighted the important interplay between commensal microorganisms and the health of their cognate hosts. Metabolites isolated from commensal bacteria have been demonstrated to possess a range of antimicrobial activities, and it is widely believed that some of these metabolites modulate host behavior, affecting predisposition to disease and pathogen invasion. Our access to the local marine mammal stranding network and previous successes in mining the fish microbiota poised us to test the hypothesis that the marine mammal microbiota is a novel source of commensal bacteria-produced bioactive metabolites...
October 18, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28991455/pyrazinoic-acid-inhibits-mycobacterial-coenzyme-a-biosynthesis-by-binding-to-aspartate-decarboxylase-pand
#16
Pooja Gopal, Wilson Nartey, Priya Ragunathan, Jansy Sarathy, Firat Kaya, Michelle Yee, Claudia Setzer, Malathy Sony Subramanian Manimekalai, Véronique Dartois, Gerhard Grüber, Thomas Dick
Previously, we showed that a major in vitro and in vivo mechanism of resistance to pyrazinoic acid (POA), the bioactive component of the critical tuberculosis (TB) prodrug pyrazinamide (PZA), involves missense mutations in the aspartate decarboxylase PanD, an enzyme required for coenzyme A biosynthesis. What is the mechanism of action of POA? Upon demonstrating that treatment of M. bovis BCG with POA resulted in a depletion of intracellular coenzyme A and confirming that this POA-mediated depletion is prevented by either missense mutations in PanD or exogenous supplementation of pantothenate, we hypothesized that POA binds to PanD and that this binding blocks the biosynthetic pathway...
October 18, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29040806/bacterial-derived-carbohydrates-bind-cyr1-and-trigger-hyphal-growth-in-candida-albicans
#17
Jason Burch, Siavash Mashayekh, Dennis D Wykoff, Catherine Leimkuhler Grimes
The dimorphic yeast Candida albicans is the most common pathologic fungus found in humans. While this species is normally commensal, a morphological switch from budding yeast to filamentous hyphae allows the fungi to invade epithelial cells and cause infections. The phenotypic change is controlled by the adenylyl cyclase, Cyr1. Interestingly, this protein contains a leucine-rich repeat (LRR) domain, which is commonly found in innate immune receptors from plants and animals. A functional and pure LRR domain was obtained in high yields from E...
October 17, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29019649/dietary-fatty-acids-control-the-species-of-n-acyl-phosphatidylethanolamines-synthesized-by-therapeutically-modified-bacteria-in-the-intestinal-tract
#18
Noura S Dosoky, Lilu Guo, Zhongyi Chen, Andrew V Feigley, Sean S Davies
Engineering the gut microbiota to produce specific beneficial metabolites represents an important new potential strategy for treating chronic diseases. Our previous studies with bacteria engineered to produce N-acyl-phosphatidylethanolamines (NAPEs), the immediate precursors of the lipid satiety factors N-acyl-ethanolamides (NAEs), found that colonization of these bacteria inhibited development of obesity in C57BL/6J mice fed a high fat diet. Individual NAE species differ in their bioactivities. Intriguingly, colonization by our engineered bacteria resulted in increased hepatic N-stearoyl-ethanolamide (C18:0NAE) levels despite the apparent inability of these bacteria to biosynthesize its precursor N-stearoyl-phosphatidylethanolamine (C18:0NAPE) in vitro...
October 17, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29035551/improved-phenoxyalkylbenzimidazoles-with-activity-against-mycobacterium-tuberculosis-appear-to-target-qcrb
#19
N Susantha Chandrasekara, Bryan J Berube, Gauri Shetye, Somsundaram Chettiar, Theresa O'Malley, Alyssa Manning, Lindsay Flint, Divya Awasthi, Thomas R Ioerger, James C Sacchettini, Thierry Masquelin, Philip A Hipskind, Joshua Odingo, Tanya Parish
The phenoxy alkyl benzimidazoles (PABs) have good anti-tubercular activity. We expanded our structure-activity relationship studies to determine the core components of PABs required for activity. The most potent compounds had minimum inhibitory concentrations against M. tuberculosis in the low nanomolar range with very little cytotoxicity against eukaryotic cells, as well as activity against intracellular bacteria. We isolated resistant mutants against PAB compounds, which had mutations in either Rv1339, of unknown function, or qcrB, a component of the cytochrome bc1 oxidase of the electron transport chain...
October 16, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28991447/rigid-oxazole-acinetobactin-analog-blocks-siderophore-cycling-in-acinetobacter-baumannii
#20
Tabbetha J Bohac, Justin A Shapiro, Timothy A Wencewicz
The emergence of multidrug resistant (MDR) Gram-negative bacterial pathogens has raised global concern. Nontraditional therapeutic strategies, including antivirulence approaches, are gaining traction as a means of applying less selective pressure for resistance in vivo. Here, we show that rigidifying the structure of the siderophore preacinetobactin from MDR Acinetobacter baumannii via oxidation of the phenolate-oxazoline moiety to a phenolate-oxazole results in a potent inhibitor of siderophore transport and imparts a bacteriostatic effect at low micromolar concentrations under infection-like conditions...
October 12, 2017: ACS Infectious Diseases
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