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ACS Infectious Diseases

Tina L Mistry, Lena Truong, Arun K Ghosh, Michael E Johnson, Shahila Mehboob
The enoyl-ACP reductase (FabI) enzyme is a well validated target for anti-staphylococcal drug discovery and development. With the goal of finding alternate therapeutics for drug resistant strains of S. aureus, such as methicillin resistant S. aureus (MRSA), our previously published series of benzimidazole-based inhibitors of the FabI enzyme from F. tularensis (FtFabI) have been evaluated against FabI from S. aureus (SaFabI). We report here the preliminary structure-activity relationship of this series and the prioritization of compounds toward lead optimization...
October 18, 2016: ACS Infectious Diseases
Dar-Chone Chow, Kacie Rice, Wanzhi Huang, Robert L Atmar, Timothy G 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...
October 18, 2016: ACS Infectious Diseases
Claire E Weston, Andreas Kraemer, 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 photoswitch embedded in the inhibitor pharmacophore: azobenzenes and arylazopyrazoles...
October 18, 2016: ACS Infectious Diseases
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 which 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 17, 2016: ACS Infectious Diseases
Ching-Wen Hou, Mackenzie L Lauro, Catherine Leimkuhler Grimes
The human body harbors over a trillion microorganisms; the innate immune system is charged with a tremendous task: to recognize "the needle in the haystack" or, in other words, to sense the pathogen in this milieu. In this viewpoint, three recent discoveries in the field of innate immunity are discussed, highlighting how in each case multiple disciplines worked together to expand the elements of the innate immune system.
October 17, 2016: ACS Infectious Diseases
Matthew A Lafreniere, Megan H Powdrill, Ragunath Singaravelu, John Paul Pezacki
Many viruses, including the hepatitis C virus (HCV), are dependent on the host RNA silencing pathway for replication. In this study, we screened small molecule probes, previously reported to disrupt loading of the RNA-induced silencing complex (RISC), including 6-hydroxydopamine (6-OHDA), suramin (SUR), and aurintricarboxylic acid (ATA), to examine their effects on viral replication. We found that 6-OHDA inhibited HCV replication; however, 6-OHDA was a less potent inhibitor of RISC than either SUR or ATA. By generating a novel chemical probe (6-OHDA-yne), we determined that 6-OHDA covalently modifies host and virus proteins...
October 13, 2016: ACS Infectious Diseases
Zhuoran Zhang, Enzhuo Yang, Chunmiao Hu, Han Cheng, Crystal Y Chen, Dan Huang, Richard Wang, Yue Zhao, Lijun Rong, Marco Vignuzzi, Hongbo Shen, Ling Shen, Zheng W Chen
While we are approaching the global eradication of circulating wild-type polioviruses(PV), vaccination with oral poliovirus vaccine (OPV) has led to emergence of circulating vaccine-derived poliovirus (cVDPV) and vaccine-associated paralytic poliomyelitis (VAPP). Complete cessation of all poliovirus infections may require stopping use of OPV and formulating improved vaccines and new antiviral drugs. Currently, no licensed drugs are available to treat chronically infected poliovirus excretors. Here, we created a modified PV expressing Gaussia Luciferase (PV-GLuc) and developed a cell-based high-throughput screening (HTS) antiviral assay...
October 12, 2016: ACS Infectious Diseases
Géraldine San Jose, Emily R Jackson, Amanda Haymond, Chinchu Johny, Rachel L Edwards, Xu Wang, R Carl Brothers, Emma K Edelstein, Audrey R Odom, Helena I Boshoff, Robin D Couch, Cynthia S Dowd
Despite continued research efforts, the threat of drug resistance from a variety of bacteria continues to plague clinical communities. Discovery and validation of novel biochemical targets will facilitate development of new drugs to combat these organisms. The methylerythritol phosphate (MEP) pathway to make isoprene units is a biosynthetic pathway essential to many bacteria. We and others have explored inhibitors of the MEP pathway as novel antibacterial agents. Mycobacterium tuberculosis, the causative agent of tuberculosis, and Yersinia pestis, resulting in the plague or "black death", both rely on the MEP pathway for isoprene production...
October 12, 2016: ACS Infectious Diseases
Tomoyo Sakata-Kato, Dyann F Wirth
Given that resistance to all drugs in clinical use has arisen, discovery of new anti-malarial 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...
October 9, 2016: ACS Infectious Diseases
Yumi Park, Angela Pacitto, Tracy Bayliss, Laura A T Cleghorn, Zhe Wang, Travis Hartman, Kriti Arora, Thomas R Ioerger, Jim Sacchettini, Menico Rizzi, Stefano Donini, Tom L Blundell, David B Ascher, Kyu Y Rhee, Ardala Breda, Nian Zhou, Veronique Dartois, Surendranadha Reddy Jonnala, Laura E Via, Valerie Mizrahi, Ola Epemolu, Laste Stojanovski, Frederick Ryan Carne Simeons, Maria Osuna-Cabello, Lucy Ellis, Claire J MacKenzie, Alasdair R C Smith, Susan Helen Davis, Dinakaran Murugesan, Kirsteen I Buchanan, Penelope A Turner, Margaret Huggett, Fabio Zuccotto, Maria Jose Rebollo-Lopez, Maria Jose Lafuente-Monasterio, Olalla Sanz, Gracia Santos Diaz, Joël Lelièvre, Lluis Ballell, Carolyn Selenski, Matthew Axtman, Sonja Ghidelli-Disse, Hannah Pflaumer, Markus Boesche, Gerard Drewes, Gail Freiberg, Matthew D Kurnick, Myron Srikumaran, Dale J Kempf, Simon R Green, Peter Christopher Ray, Kevin D Read, Paul G Wyatt, Clifton E Barry Rd, Helena I M Boshoff
A potent, non-cytotoxic indazole sulfonamide was identified by high-throughput screening of >100,000 synthetic compounds for activity against Mycobacterium tuberculosis (Mtb). This non-cytotoxic compound did not directly inhibit cell wall biogenesis but triggered a slow lysis of Mtb cells as measured by release of intracellular green fluorescent protein (GFP). Isolation of resistant mutants followed by whole-genome sequencing showed an unusual gene amplification of a 40 gene region spanning Rv3371 to Rv3411c and in one case a potential promoter mutation upstream of guaB2 (Rv3411c) encoding inosine monophosphate dehydrogenase (IMPDH)...
October 5, 2016: ACS Infectious Diseases
Maaran Michael Rajah, Ryan D Pardy, Stephanie A Condotta, Martin J Richer, Selena Michael Sagan
Zika virus (ZIKV) is an emerging arthropod-borne pathogen that has recently gained notoriety due to its rapid and ongoing geographic expansion and its novel association with neurological complications. Reports of ZIKV associated Guillain-Barré syndrome as well as fetal microcephaly place emphasis on the need to develop preventative measures and therapeutics to combat ZIKV infection. Thus, it is imperative that models to study ZIKV replication, pathogenesis, and the immune response are developed in conjunction with integrated vector control strategies to mount an efficient response to the pandemic...
October 5, 2016: ACS Infectious Diseases
Joanna C Evans, Carolina Trujillo, Zhe Wang, Hyungjin Eoh, Sabine Ehrt, Dirk Schnappinger, Helena I M Boshoff, Kyu Y Rhee, Clifton E Barry, Valerie Mizrahi
Mycobacterium tuberculosis relies on its own ability to biosynthesize coenzyme A to meet the needs of the myriad enzymatic reactions that depend on this cofactor for activity. As such, the essential pantothenate and coenzyme A biosynthesis pathways have attracted attention as targets for tuberculosis drug development. To identify the optimal step for coenzyme A pathway disruption in M. tuberculosis, we constructed and characterized a panel of conditional knockdown mutants in coenzyme A pathway genes. Here, we report that silencing of coaBC was bactericidal in vitro, whereas silencing of panB, panC, or coaE was bacteriostatic over the same time course...
October 5, 2016: ACS Infectious Diseases
Marianne Ngure, Moheshwarnath Issur, Nikoloz Shkriabai, Hsiao-Wei Liu, Gonzalo Cosa, Mamuka Kvaratskhelia, Matthias Götte
Domain II of the nonstructural protein 5 (NS5A) of the hepatitis C virus (HCV) is involved in intermolecular interactions with the viral RNA genome, the RNA-dependent RNA polymerase NS5B, and the host factor cyclophilin A (CypA). However, domain II of NS5A (NS5A(DII)) is largely disordered, which makes it difficult to characterize the protein-protein or protein-nucleic acid interfaces. Here we utilized a mass spectrometry-based protein footprinting approach in attempts to characterize regions forming contacts between NS5A(DII) and its binding partners...
October 5, 2016: ACS Infectious Diseases
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...
October 4, 2016: ACS Infectious Diseases
Margaret A Phillips, Karen L White, Sreekanth Kokkonda, Xiaoyi Deng, John White, Farah El Mazouni, Kennan Marsh, Diana R Tomchick, Krishne Manjalanagara, Kakali Rani Rudra, Grennady Wirjanata, Rintis Noviyanti, Ric N Price, Jutta Marfurt, David M Shackleford, Francis C K Chiu, Michael Campbell, Maria Belen Jimenez-Diaz, Santiago Ferrer Bazaga, Iñigo Angulo-Barturen, Maria Santos Martinez, Maria Lafuente-Monasterio, Werner Kaminsky, Kigbafori Silue, Anne-Marie Zeeman, Clemens Kocken, Didier Leroy, Benjamin Blasco, Emilie Rossignol, Thomas Rueckle, Dave Matthews, Jeremy N Burrows, David Waterson, Michael J Palmer, Pradipsinh K Rathod, Susan A Charman
The emergence of drug-resistant malaria parasites continues to hamper efforts to control this lethal disease. Dihydroorotate dehydrogenase has recently been validated as a new target for the treatment of malaria, and a selective inhibitor (DSM265) of the Plasmodium enzyme is currently in clinical development. With the goal of identifying a backup compound to DSM265, we explored replacement of the SF5-aniline moiety of DSM265 with a series of CF3-pyridinyls while maintaining the core triazolopyrimidine scaffold...
October 4, 2016: ACS Infectious Diseases
Katie R Tallman, Samantha R Levine, Kimberly Elizabeth Beatty
Mycobacterium tuberculosis (Mtb) is the deadliest bacterial pathogen in the world. An estimated one-third of humans harbor Mtb in a dormant state. These asymptomatic, latent infections impede tuberculosis eradication due to the long-term potential for reactivation. Dormant Mtb has reduced enzymatic activity, but hydrolases that remain active facilitate pathogen survival. We targeted Mtb esterases, a diverse set of enzymes in the serine hydrolase family, and studied their activities using both activity-based probes (ABPs) and fluorogenic esterase substrates...
October 3, 2016: ACS Infectious Diseases
Sabrina Lusvarghi, Katheryn Lohith, Jeanne Morin-Leisk, Rodolfo Ghirlando, Jenny E Hinshaw, Carole A Bewley
Carbohydrate binding proteins such as griffithsin, cyanovirin-N, and BanLec are potent HIV entry inhibitors and promising microbicides. Each binds to high-mannose glycans on the surface envelope glycoprotein gp120, yet the mechanisms by which they engage viral spikes and exhibit inhibition constants ranging from nanomolar to picomolar are not understood. To determine the structural and mechanistic basis for recognition and potency, we selected a panel of lectins possessing different valencies per subunit, oligomeric states, and relative orientations of carbohydrate binding sites to systematically probe their contributions to inhibiting viral entry...
October 3, 2016: ACS Infectious Diseases
Shilah A Bonnett, Juliane Ollinger, Susantha Chandrasekera, Stephanie Florio, Theresa O'Malley, Megan Files, Jo-Ann Jee, James Ahn, Allen Casey, Yulia Ovechkina, David Roberts, Aaron Korkegian, Tanya Parish
The general secretion (Sec) pathway is a conserved essential pathway in bacteria and is the primary route of protein export across the cytoplasmic membrane. During protein export, the signal peptidase LepB catalyzes the cleavage of the signal peptide and subsequent release of mature proteins into the extracellular space. We developed a target-based whole cell assay to screen for potential inhibitors of LepB, the sole signal peptidase in Mycobacterium tuberculosis, using a strain engineered to underexpress LepB (LepB-UE)...
September 19, 2016: ACS Infectious Diseases
Matthew Sievers Alkaitis, Hans C Ackerman
Tetrahydrobiopterin (BH4) is an essential cofactor for both phenylalanine hydroxylase and nitric oxide synthase. Patients with severe malaria have low urinary BH4, elevated plasma phenylalanine, and impaired endothelium-dependent vasodilation, suggesting that BH4 depletion may limit phenylalanine metabolism and nitric oxide synthesis. We infected C57BL/6 mice with Plasmodium berghei ANKA to characterize BH4 availability and to investigate the effects of BH4 supplementation. P. berghei ANKA infection lowered BH4 in plasma, erythrocytes and brain tissue, but raised it in aorta and liver tissue...
September 19, 2016: ACS Infectious Diseases
Vinayak Singh, Stefano Donini, Angela Pacitto, Claudia Sala, Ruben C Hartkoorn, Neeraj Dhar, Gyorgy Keri, David B Ascher, Guillaume Mondésert, Anthony Vocat, Andréanne Lupien, Raphael Sommer, Hélène Vermet, Sophie Lagrange, Joe Buechler, Digby F Warner, John D McKinney, Janos Pato, Stewart T Cole, Tom L Blundell, Menico Rizzi, Valerie Mizrahi
VCC234718, a molecule with growth inhibitory activity against Mycobacterium tuberculosis (Mtb), was identified by phenotypic screening of a 15344-compound library. Sequencing of a VCC234718-resistant mutant identified a Y487C substitution in the inosine monophosphate dehydrogenase, GuaB2, which was subsequently validated to be the primary molecular target of VCC234718 in Mtb. VCC234718 inhibits Mtb GuaB2 with a Ki of 100 nM and is uncompetitive with respect to IMP and NAD(+). This compound binds at the NAD(+) site, after IMP has bound, and makes direct interactions with IMP; therefore, the inhibitor is by definition uncompetitive...
September 8, 2016: ACS Infectious Diseases
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