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ACS Infectious Diseases

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https://www.readbyqxmd.com/read/28103015/antimicrobial-activity-ame-resistance-and-translation-inhibition-studies-of-anthraquinone-neomycin-conjugates
#1
Natalya N Degtyareva, Changjun Gong, Sandra Story, Nathanael Levinson, Adegboyega K Oyelere, Keith D Green, Sylvie Garneau-Tsodikova, Dev Priya Arya
The antibacterial effects of aminoglycosides are based on their association with the A-site of bacterial ribosomal RNA 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...
January 19, 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
#2
Malak Haidar, Anne Lombes, 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 non-phosphorylatable BAD substrate that inhibits endogenous S155 phosphorylation, leading to complex dissociation and ubiquitination and degradation of HK2 by the proteasome...
January 13, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28075113/pseudomonas-aeruginosa-lasr%C3%A2-dna-binding-is-directly-inhibited-by-quorum-sensing-antagonists
#3
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
#4
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
#5
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/27764938/1-2-4-triazolidine-3-thiones-have-specific-activity-against-acinetobacter-baumannii-among-common-nosocomial-pathogens
#6
Brendan W Corey, Mitchell G Thompson, Lauren E Hittle, Anna C Jacobs, Edward A Asafo-Adjei, William M Huggins, Roberta J Melander, Christian Melander, Robert K Ernst, Daniel V Zurawski
Acinetobacter baumannii are Gram-negative bacilli that pose a constant threat to susceptible patients because of increased resistance to multiple antibiotics and persistence in the hospital environment. After genome analysis, we discovered that A. baumannii harbors genes that share homology to an enzymatic pathway that elongates long-chain fatty acids (LCFA) in fungi. Previously, 1,2,4-triazolidine-3-thiones (T-3-Ts) were shown to inhibit hyphae production in fungi, and this same LCFA elongation pathway was implicated as the possible target...
November 3, 2016: ACS Infectious Diseases
https://www.readbyqxmd.com/read/27768847/reviving-antibiotics-efflux-pump-inhibitors-that-interact-with-acra-a-membrane-fusion-protein-of-the-acrab-tolc-multidrug-efflux-pump
#7
Narges Abdali, Jerry M Parks, Keith M Haynes, Julie L Chaney, Adam T Green, David Wolloscheck, John K Walker, Valentin V Rybenkov, Jerome Baudry, Jeremy C Smith, Helen I Zgurskaya
Antibiotic resistance is a major threat to human welfare. Inhibitors of multidrug efflux pumps (EPIs) are promising alternative therapeutics that could revive activities of antibiotics and reduce bacterial virulence. Identification of new druggable sites for inhibition is critical for the development of effective EPIs, especially in light of constantly emerging resistance. Here, we describe EPIs that interact with periplasmic membrane fusion proteins, critical components of efflux pumps that are responsible for the activation of the transporter and the recruitment of the outer-membrane channel...
November 2, 2016: ACS Infectious Diseases
https://www.readbyqxmd.com/read/27756124/toward-photopharmacological-antimicrobial-chemotherapy-using-photoswitchable-amidohydrolase-inhibitors
#8
Claire E Weston, Andreas Krämer, Felix Colin, Özkan Yildiz, Matthias G J Baud, Franz-Josef Meyer-Almes, Matthew J Fuchter
Photopharmacological agents exhibit light-dependent biological activity and may have potential in the development of new antimicrobial agents/modalities. Amidohydrolase enzymes homologous to the well-known human histone deacetylases (HDACs) are present in bacteria, including resistant organisms responsible for a significant number of hospital-acquired infections and deaths. We report photopharmacological inhibitors of these enzymes, using two classes of photoswitches embedded in the inhibitor pharmacophore: azobenzenes and arylazopyrazoles...
October 31, 2016: ACS Infectious Diseases
https://www.readbyqxmd.com/read/27748583/molecular-recognition-of-muramyl-dipeptide-occurs-in-the-leucine-rich-repeat-domain-of-nod2
#9
Mackenzie L Lauro, Elizabeth A D'Ambrosio, Brian J Bahnson, Catherine Leimkuhler Grimes
Genetic mutations in the innate immune receptor nucleotide-binding oligomerization domain-containing 2 (Nod2) have demonstrated increased susceptibility to Crohn's disease, an inflammatory bowel disease that is hypothesized to be accompanied by changes in the gut microbiota. Nod2 responds to the presence of bacteria, specifically a fragment of the bacterial cell wall, muramyl dipeptide (MDP). The proposed site of this interaction is the leucine-rich repeat (LRR) domain. Surface plasmon resonance and molecular modeling were used to investigate the interaction of the LRR domain with MDP...
October 31, 2016: ACS Infectious Diseases
https://www.readbyqxmd.com/read/27788579/inhibition-of-diacylglycerol-transferase-1-has-potent-antiviral-effect-on-hepatitis-c-virus-in-vitro-but-not-in-patients-in-a-randomized-trial
#10
Edward Gane, Catherine Stedman, Kiran Dole, Jin Chen, Charles Daniel Meyers, Brigitte Wiedmann, Jin Zhang, Prakash Raman, Richard A Colvin
Hepatitis C virus (HCV) infection is a significant cause of liver disease affecting 80-150 million people globally. Diacylglycerol transferase-1 (DGAT-1), a triglyceride synthesis enzyme, is important for the HCV life-cycle in vitro. Pradigastat, a potent DGAT-1 inhibitor found to lower triglycerides and HgbA1c in patients, was investigated for safety and efficacy in patients with HCV. This was a two-part study. In the in vitro study, the effect of pradigastat on virus production was evaluated in infected cells in culture...
October 27, 2016: ACS Infectious Diseases
https://www.readbyqxmd.com/read/27785912/structural-and-biochemical-characterization-of-acinetobacter-spp-aminoglycoside-acetyltransferases-highlights-functional-and-evolutionary-variation-among-antibiotic-resistance-enzymes
#11
Peter J Stogios, Misty Lee Kuhn, Elena Evdokimova, Melissa Law, Patrice Courvalin, Alexei Savchenko
Modification of aminoglycosides by N-acetyltransferases (AACs) is one of the major mechanisms of resistance to these antibiotics in human bacterial pathogens. More than fifty enzymes belonging to the AAC(6') subfamily have been identified in Gram-negative and Gram-positive clinical isolates. Our understanding of the molecular function and evolutionary origin of these resistance enzymes remains incomplete. Here we report the structural and enzymatic characterization of AAC(6')-Ig and AAC(6')-Ih from Acinetobacter spp...
October 27, 2016: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28081610/the-bare-essentials-of-antibiotic-target-validation
#12
Lizbeth Hedstrom
The convergence of competitive fitness experiments and phenotypic screening would seem to be an auspicious beginning for validation of an antibacterial target. IMPDH was already identified an essential protein in Mycobacterium tuberculosis when not one, but two, groups discovered inhibitors with promising antitubercular activity. A new target appeared to be born. Surprisingly, the two groups came to completely different conclusions about the vulnerability of IMPDH and its future as a drug target. This viewpoint discusses these papers and how to resolve this conundrum...
January 13, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28081609/in-this-issue
#13
Lorraine Clark
No abstract text is available yet for this article.
January 13, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28081608/dynamic-interconversions-of-hcv-helicase-binding-modes-on-the-nucleic-acid-substrate
#14
Christopher J Ablenas, Hsiao-Wei Liu, Nikoloz Shkriabai, Mamuka Kvaratskhelia, Gonzalo Cosa, Matthias Götte
The dynamics involved in the interaction between hepatitis C virus nonstructural protein 3 (NS3) C-terminal helicase and its nucleic acid substrate have been the subject of interest for some time given the key role of this enzyme in viral replication. Here, we employed fluorescence-based techniques and focused on events that precede the unwinding process. Both ensemble Förster resonance energy transfer (FRET) and ensemble protein induced fluorescence enhancement (PIFE) assays show binding on the 3' single-stranded overhang of model DNA substrates (>5 nucleotides) with no preference for the single-stranded/double-stranded (ss/ds) junction...
January 13, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28081607/structure-activity-relationships-of-spectinamide-antituberculosis-agents-a-dissection-of-ribosomal-inhibition-and-native-efflux-avoidance-contributions
#15
Jiuyu Liu, David F Bruhn, Robin B Lee, Zhong Zheng, Tanja Janusic, Dimitri Scherbakov, Michael S Scherman, Helena I Boshoff, Sourav Das, Rakesh, Samanthi L Waidyarachchi, Tiffany A Brewer, Begoña Gracia, Lei Yang, John Bollinger, Gregory T Robertson, Bernd Meibohm, Anne J Lenaerts, Jose Ainsa, Erik C Böttger, Richard E Lee
Spectinamides are a novel class of antitubercular agents with the potential to treat drug-resistant tuberculosis infections. Their antitubercular activity is derived from both ribosomal affinity and their ability to overcome intrinsic efflux mediated by the Mycobacterium tuberculosis Rv1258c efflux pump. This study explores the structure-activity relationships through analysis of 50 targeted spectinamides. Compounds are evaluated for ribosomal translational inhibition, MIC activity in Rv1258c efflux pump deficient and wild type tuberculosis strains, and efficacy in an acute model of tuberculosis infection...
January 13, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/27798837/biochemical-and-structural-characterization-of-selective-allosteric-inhibitors-of-the-plasmodium-falciparum-drug-target-prolyl-trna-synthetase
#16
Stephen Nakazawa Hewitt, David M Dranow, Benjamin G Horst, Jan A Abendroth, Barbara Forte, Irene Hallyburton, Chimed Jansen, Beatriz Baragaña, Ryan Choi, Kasey L Rivas, Matthew A Hulverson, Mitchell Dumais, Thomas E Edwards, Donald D Lorimer, Alan H Fairlamb, David W Gray, Kevin D Read, Adele M Lehane, Kiaran Kirk, Peter J Myler, Amy Wernimont, Chris Walpole, Robin Stacy, Lynn K Barrett, Ian H Gilbert, Wesley C Van Voorhis
Plasmodium falciparum (Pf) prolyl-tRNA synthetase (ProRS) is one of the few chemical-genetically validated drug targets for malaria, yet highly selective inhibitors have not been described. In this paper, approximately 40,000 compounds were screened to identify compounds that selectively inhibit PfProRS enzyme activity versus Homo sapiens (Hs) ProRS. X-ray crystallography structures were solved for apo, as well as substrate- and inhibitor-bound forms of PfProRS. We identified two new inhibitors of PfProRS that bind outside the active site...
January 13, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/27931103/in-this-issue
#17
Janice Elaine Y Silverman
No abstract text is available yet for this article.
December 9, 2016: ACS Infectious Diseases
https://www.readbyqxmd.com/read/27756125/engineering-specificity-from-broad-to-narrow-design-of-a-%C3%AE-lactamase-inhibitory-protein-blip-variant-that-exclusively-binds-and-detects-kpc-%C3%AE-lactamase
#18
Dar-Chone Chow, Kacie Rice, Wanzhi Huang, Robert L Atmar, Timothy Palzkill
The β-lactamase inhibitory protein (BLIP) binds and inhibits a wide range of class A β-lactamases including the TEM-1 β-lactamase (Ki = 0.5 nM), which is widely present in Gram-negative bacteria, and the KPC-2 β-lactamase (Ki = 1.2 nM), which hydrolyzes virtually all clinically useful β-lactam antibiotics. The extent to which the specificity of a protein that binds a broad range of targets can be modified to display narrow specificity was explored in this study by engineering BLIP to bind selectively to KPC-2 β-lactamase...
December 9, 2016: ACS Infectious Diseases
https://www.readbyqxmd.com/read/27718558/a-novel-methodology-for-bioenergetic-analysis-of-plasmodium-falciparum-reveals-a-glucose-regulated-metabolic-shift-and-enables-mode-of-action-analyses-of-mitochondrial-inhibitors
#19
Tomoyo Sakata-Kato, Dyann F Wirth
Given that resistance to all drugs in clinical use has arisen, discovery of new antimalarial drug targets is eagerly anticipated. The Plasmodium mitochondrion has been considered a promising drug target largely based on its significant divergence from the host organelle as well as its involvement in ATP production and pyrimidine biosynthesis. However, the functions of Plasmodium mitochondrial protein complexes and associated metabolic pathways are not fully characterized. Here, we report the development of novel and robust bioenergetic assay protocols for Plasmodium falciparum asexual parasites utilizing a Seahorse Bioscience XFe24 Extracellular Flux Analyzer...
December 9, 2016: ACS Infectious Diseases
https://www.readbyqxmd.com/read/27696820/virus-like-particle-display-of-the-%C3%AE-gal-epitope-for-the-diagnostic-assessment-of-chagas-disease
#20
Carlos Ramon Nascimento Brito, Craig S McKay, Maíra Araújo Azevedo, Luíza Costa Brandão Santos, Ana Paula Venuto, Daniela Ferreira Nunes, Daniella Alchaar D'Ávila, Gisele Macedo Rodrigues da Cunha, Igor Correia Almeida, Ricardo Tostes Gazzinelli, Lucia Maria Cunha Galvão, Egler Chiari, Carlos A Sanhueza, M G Finn, Alexandre Ferreira Marques
The α-Gal antigen [Galα(1,3)Galβ(1,4)GlcNAcα] is an immunodominant epitope displayed by infective trypomastigote forms of Trypanosoma cruzi, the causative agent of Chagas disease. A virus-like particle displaying a high density of α-Gal was found to be a superior reagent for the ELISA-based serological diagnosis of Chagas disease and the assessment of treatment effectiveness. A panel of sera from patients chronically infected with T. cruzi, both untreated and benznidazole-treated, was compared with sera from patients with leishmaniasis and from healthy donors...
December 9, 2016: ACS Infectious Diseases
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