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ACS Infectious Diseases

Zhongrui Ma, Huajie Zhang, Lei Li, Min Chen, Peng George Wang
Bacterial pathogen infections are fast-growing public health threats and worldwide problems. Glycoconjugate vaccines are among the most effective means in combating such infections. Recent advances in bacterial protein glycan coupling technology (PGCT) have revolutionized the production of glycoconjugate vaccines, and draw enormous attention from both researchers and pharmaceutical companies. Cloning of bacterial surface polysaccharide gene cluster is a prerequisite for the application of PGCT. In this study, we applied RecET direct cloning strategy for rapid and efficient cloning of O-antigen polysaccharide gene clusters from Escherichia coli serotypes O25b, O26 and O55 in a high-fidelity manner...
November 16, 2018: ACS Infectious Diseases
Veronica Hubble, Brittany A Hubbard, Bradley Minrovic, Roberta Melander, Christian Melander
A major contributor to fatality in cystic fibrosis (CF) patients stems from infection with the opportunistic bacterium Pseudomonas aeruginosa. As a result of the CF patient's vulnerability to bacterial infections, one of the main treatment focuses is antibiotic therapy. However, the highly adaptive nature of P. aeruginosa, in addition to the intrinsic resistance to many antibiotics exhibited by most Gram-negative bacteria, means that multi-drug resistant (MDR) strains are increasingly prevalent. This makes eradication of pseudomonal lung infections nearly impossible once the infection becomes chronic...
November 16, 2018: ACS Infectious Diseases
Valerian Pasche, Benoît Laleu, Jennifer Keiser
As part of the control and elimination strategy of human schistosomiasis, preventive chemotherapy relies on a single drug, praziquantel. Facing an almost dry drug development pipeline, screening the Pathogen Box from the Medicines for Malaria Venture (MMV), provides a unique opportunity to possibly expand the pool of potent molecules against schistosomiasis. The activity of 400 compounds from this open-access library was first screened in vitro on the larval stage of Schistosoma mansoni. The hits were then tested on adult worms...
November 6, 2018: ACS Infectious Diseases
Lei Deng, Bao-Zhong Wang
Annually recurring seasonal influenza causes massive economic loss and poses severe threats to public health worldwide. The current seasonal influenza vaccines are the most effective means of preventing influenza infections but possess major weaknesses. Seasonal influenza vaccines require annual updating of the vaccine strains. However, it is an unreachable task to accurately predict the future circulating strains. Vaccines with mismatched strains dramatically compromise the vaccine efficacy. In addition, the seasonal influenza vaccines are ineffective against an unpredictable pandemic...
November 15, 2018: ACS Infectious Diseases
Simon Leiris, Alicia Coelho, Jérôme Castandet, Maëlle Bayet, Clarisse Lozano, Juliette Bougnon, Justine Bousquet, Martin John Everett, Marc Lemonnier, Nicolas Sprynski, Magdalena Zalacain, Thomas David Pallin, Michael Cramp, Neil Jennings, Gilles Raphy, Mark William Jones, Ramesh Pattipati, Battu Shankar, Relangi Sivasubrahmanyam, Ashok Kumar Soodhagani, Ramakrishna Reddy Juventhala, Narender Pottabathini, Srinivasu Pothukanuri, Manuela Benvenuti, Cecilia Pozzi, Stefano Mangani, Filomena De Luca, Giulia Cerboni, Jean-Denis Docquier, David Davies
The clinical effectiveness of carbapenem antibiotics such as meropenem is becoming increasingly compromised by the spread of both metallo β-lactamase (MBL) and serine β-lactamase (SBL) enzymes on mobile genetic elements, stimulating research to find new β-lactamase inhibitors to be used in conjunction with carbapenems and other β-lactam antibiotics. Herein we describe our initial exploration of a novel chemical series of metallo β-lactamase inhibitors, from concept through to efficacy in a survival model using an advanced tool compound (ANT431) in conjunction with meropenem...
November 14, 2018: ACS Infectious Diseases
Pasquale Linciano, Laura Cendron, Eleonora Gianquinto, Francesca Spyrakis, Donatella Tondi
The worldwide emergence of metallo β-lactamase NDM-1 as carbapenemase able to hydrolyze near all available β-lactam antibiotics has characterized the last decade, endangering efficacious antibacterial treatments. No inhibitors for NDM-1 are available in therapy, nor promising compounds are in the pipeline for future NDM-1 inhibitors. We report the studies dedicated to the design and development of effective NDM-1 inhibitors. The discussion for each agent moves from the employed design strategy to the ability of the identified inhibitor to synergize β-lactam antibiotics...
November 13, 2018: ACS Infectious Diseases
Victoriano Corpas-Lopez, Sonia Moniz, Michael Thomas, Richard J Wall, Leah S Torrie, Dorothea Zander-Dinse, Michele Tinti, Stephen Brand, Laste Stojanovski, Sujatha Manthri, Irene Hallyburton, Fabio Zuccotto, Paul G Wyatt, Manu De Rycker, David Horn, Michael A J Ferguson, Joachim Clos, Kevin D Read, Alan H Fairlamb, Ian H Gilbert, Susan Wyllie
Visceral leishmaniasis (VL), caused by the protozoan parasites Leishmania donovani and L. infantum, is responsible for ∼30 000 deaths annually. Available treatments are inadequate, and there is a pressing need for new therapeutics. N-Myristoyltransferase (NMT) remains one of the few genetically validated drug targets in these parasites. Here, we sought to pharmacologically validate this enzyme in Leishmania. A focused set of 1600 pyrazolyl sulfonamide compounds was screened against L. major NMT in a robust high-throughput biochemical assay...
November 12, 2018: ACS Infectious Diseases
Nathan P Lavey, Tyler Shadid, Jimmy Ballard, Adam S Duerfeldt
Caseinolytic protease P (ClpP) has emerged as a promising new target for antibacterial development. While ClpPs from single isoform expressing bacteria have been studied in detail, the function and regulation of systems with more than one ClpP homolog are still poorly understood. Herein, we present fundamental studies towards understanding the ClpP system in C. difficile, an anaerobic spore forming pathogen that contains two chromosomally distant isoforms of ClpP. Examination of proteomic and genomic data suggest that ClpP1 is the primary isoform responsible for normal growth and virulence, but little is known about the function of ClpP2 or the context required for the formation of functional proteases...
November 9, 2018: ACS Infectious Diseases
Benjamin M Fontaine, Yashasvika Duggal, Emily E Weinert
The survival of all organisms depends on implementation of appropriate phenotypic responses upon perception of relevant environmental stimuli. Sensory inputs are propagated via interconnected biochemical and/or electrical cascades mediated by diverse signaling molecules, including gases, metal cations, lipids, peptides, and nucleotides. These networks often comprise second messenger signaling systems in which a ligand (the primary messenger) binds to an extracellular receptor, thereby altering the intracellular concentration of a second messenger molecule which ultimately modulates gene expression through interaction with various effectors...
November 9, 2018: ACS Infectious Diseases
Xin Ye, Chise Tateno, Emily P Thi, Masakazu Kakuni, Nicholas M Snead, Yuji Ishida, Trisha R Barnard, Michael Sofia, Takashi Shimada, Amy C H Lee
Hepatitis delta virus (HDV) infects 10-20 million individuals worldwide and causes severe fulminant hepatitis with high likelihood of cirrhosis and hepatocellular carcinoma. HDV infection cannot occur in the absence of the surface antigen (HBsAg) of the hepatitis B virus. RNA interference is an effective mechanism by which to inhibit viral transcripts and siRNA therapeutics sharing this mechanism have begun to demonstrate clinical efficacy. Here we assessed the outcome of HBV-targeting siRNA intervention against HDV and compared it to a direct anti-HDV siRNA approach in dually-infected humanized mice...
November 8, 2018: ACS Infectious Diseases
M Nurul Islam, Reese Hitchings, Santosh Kumar, Fabio Levi Fontes, J Shaun Lott, Nicole A Kruh-Garcia, Dean C Crick
The biosynthesis of tryptophan in Mycobacterium tuberculosis is initiated by the transformation of chorismate to anthranilate, catalysed by anthranilate synthase (TrpE/TrpG). Five additional enzymes are required to complete tryptophan biosynthesis. M. tuberculosis strains auxotrophic for tryptophan, an essential amino acid in the human diet, are avirulent. Thus, tryptophan synthesis in M. tuberculosis has been suggested as a potential drug target and it has been reported that fluorinated anthranilate is lethal to the bacillus...
November 8, 2018: ACS Infectious Diseases
Emily P Thi, Ammen P Dhillon, Andrzej Ardzinski, Lale Bidirici-Ertekin, Kyle D Cobarrubias, Andrea Cuconati, Andrew S Kondratowicz, Kaylyn Kwak, Alice H L Li, Angela Miller, Chris Pasetka, Luying Pei, Janet R Phelps, Nicholas M Snead, Xiaohe Wang, Xin Ye, Michael Sofia, Amy C H Lee
Current approved nucleoside analog treatments for chronic hepatitis B virus infection are effective at controlling viral titre but are not curative and have minimal impact on the production of viral proteins such as surface antigen (HBsAg), the HBV envelope protein believed to play a role in maintaining the immune tolerant state required for viral persistence. Novel agents are needed to effect HBV cure, and reduction of HBV antigenemia may potentiate activation of effective and long-lasting host immune control...
November 7, 2018: ACS Infectious Diseases
Yue-Juan Zhang, Wen-Ming Wang, Peter Oelschlaeger, Cheng Chen, Jin-E Lei, Miao Lv, Ke-Wu Yang
The "superbug" infection caused by New Delhi metallo-β-lactamase (NDM-1) has become an emerging threat. Monitoring NDM-1 has proven challenging due to its shuttling between pathogenic bacteria. Here, we report an isothermal titration calorimetry (ITC) method that can monitor activity and inhibition of NDM-1 in live bacterial cells in real time. This method has been exemplified by monitoring of the activity and inhibition of the target enzyme and evaluating the breakdown of antibiotics by pathogenic bacteria expressing β-lactamases...
November 5, 2018: ACS Infectious Diseases
Sarah L Keasey, Jessica L Smith, Stefan Fernandez, Anna P Durbin, Bryan M Zhao, Robert G Ulrich
Dengue is a mosquito-borne disease caused by four dengue virus serotypes (DENV1-4) that are loosely categorized by sequence commonalities and antibody recognition profiles. The highly variable envelope protein (E) that is prominently displayed on the surface of DENV is an essential component of vaccines currently under development, yet the impact of using single strains to represent each serotype in tetravalent vaccines has not been adequately studied. We synthesized chimeric E by replacing highly variable residues from a dengue virus serotype 2 vaccine strain (PUO-218) with those from 16 DENV2 lineages spanning 60 years of antigen evolution...
November 5, 2018: ACS Infectious Diseases
Joshua A Jackman, Pei-Yong Shi, Nam-Joon Cho
Mosquito-borne viruses encompass a wide range of pathogens, such as dengue and Zika viruses, that often cocirculate geographically. These viruses affect hundreds of millions of people worldwide, yet no clinically approved therapy is currently available for treating these viral infections. Thus, innovative therapies, especially inhibitors with broad antiviral activities against all these viruses, are urgently needed. While traditional therapeutic strategies mainly focus on inhibiting viral replication in a "one lock, one key" manner (e...
November 2, 2018: ACS Infectious Diseases
Marlon H Cardoso, Elizabete S Cândido, Lai Y Chan, Marcelo Der Torossian Torres, Karen G N Oshiro, Samilla B Rezende, William F Porto, Timothy K Lu, Cesar de la Fuente-Nunez, David J Craik, Octávio L Franco
Computer-aided screening of antimicrobial peptides (AMPs) is a promising approach for discovering novel therapies against multidrug-resistant bacterial infections. Here, we functionally and structurally characterized an Escherichia coli-derived AMP (EcDBS1R5) previously designed through pattern identification [α-helical set (KK[ILV](3) [AILV])], followed by sequence optimization. EcDBS1R5 inhibited the growth of Gram-negative and Gram-positive, susceptible and resistant bacterial strains at low doses (2-32 μM), with no cytotoxicity observed against non-cancerous and cancerous cell lines in the concentration range analyzed (<100 μM)...
November 1, 2018: ACS Infectious Diseases
John White, Satish Dhingra, Xiaoyi Deng, Farah El Mazouni, Marcus Lee, Gustavo Afanador, Aloysus Lawong, Diana R Tomchick, Caroline L Ng, Jade Bath, Pradipsinh K Rathod, David A Fidock, Margaret A Phillips
Malaria is one of the most challenging human infectious diseases and both prevention and control have been hindered by the development of Plasmodium falciparum resistance to existing therapies. Several new compounds with novel mechanisms are in clinical development for the treatment of malaria including DSM265, an inhibitor of Plasmodium dihydroorotate dehydrogenase. In order to explore the mechanisms by which resistance might develop to DSM265 in the field, we selected for DSM265-resistant P. falciparum parasites in vitro...
October 30, 2018: ACS Infectious Diseases
Yuan Liu, Meirong Song, Shuangyang Ding, Kui Zhu
The development and rapid spread of multi-drug resistant (MDR) bacteria causes a severe public crisis. New antibacterial compounds are urgently needed to treat bacterial infections. By circumventing the disadvantages of cationic peptides, here we engineered a short, linear, low cationic peptide bacaucin-1a, which exhibited remarkable antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). Bacaucin-1a was efficient to prevent MRSA associated infections in both in vitro and in vivo models with unique mode of action...
October 29, 2018: ACS Infectious Diseases
Kelly M Craft, Harrison C Thomas, Steven D Townsend
For newborns, human milk oligosaccharides (HMOs) serve as an important source of protection against bacterial pathogens. HMOs  prevent infection by functioning as decoy receptors that bind pathogens to inhibit cellular adhesion. HMOs also play a protective role by acting as prebiotics that selectively promote the growth of symbiotic gut bacteria over pathogens. Fucosylated HMOs in particular are well-known for their roles as both decoy receptors and prebiotics. Recently, we discovered that HMOs possess antimicrobial activity against Group B Streptococcus (GBS) by increasing cellular permeability...
October 25, 2018: ACS Infectious Diseases
Surabhi Lavania, Ritu Das, Abhijeet Dhiman, Vithal Prasad Myneedu, Ajoy Verma, Nagendra Singh, Tarun Kumar Sharma, Jaya Sivaswami Tyagi
Pulmonary tuberculosis is the most common manifestation of tuberculosis, and to this day, sputum smear microscopy remains the most widely used diagnostic test in resource-limited settings despite its suboptimal sensitivity. Here we report the development of two DNA aptamer-based diagnostic tests, namely aptamer linked immobilized sorbent assay (Aptamer ALISA) and electrochemical sensor (ECS), for the direct detection of a TB biomarker HspX in sputum. First we compared the performance of Aptamer ALISA with anti-HspX polyclonal antibody-based enzyme linked immunosorbent assay (Antibody ELISA) in a blinded study of 314 sputum specimens...
October 25, 2018: ACS Infectious Diseases
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