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ACS Infectious Diseases

Liben Chen, Dong Jin Shin, Shuyu Zheng, Johan H Melendez, Charlotte Gaydos, Tza-Huei Wang
Multidrug-resistant gonorrhea has become an urgent issue for global public health. As the causative agent of gonorrhea ─ Neisseria gonorrhoeae ─ has been progressively developing resistance to nearly all prescribed antimicrobial drugs, monitoring its antimicrobial resistance on a broader scale has become a crucial agenda for effective antibiotic stewardship. Unfortunately, gold standard antimicrobial susceptibility testing (AST) relies on time and labor-intensive phenotypic assays, which lag behind the current diagnostic workflow for N...
July 12, 2018: ACS Infectious Diseases
Josh Radke, Jeremy N Burrows, Daniel E Goldberg, L David Sibley
Toxoplasma gondii is a common zoonotic infection of humans and estimates indicate that 1-2 billion people are chronically infected. Although largely asymptomatic, chronic infection poses risk of serious disease due to reactivation should immunity decline. Current therapies for toxoplasmosis only control acute infection caused by actively proliferating tachyzoites but do not eradicate the chronic tissue cyst stages. As well, there are considerable adverse side effects of the most commonly used therapy of combined sulfadiazine and pyrimethamine...
July 12, 2018: ACS Infectious Diseases
Christopher T Walsh
Natural products with anti-infective activity are largely of polyketide or peptide origin. The nascent scaffolds typically undergo further enzymatic morphing to produce mature active structures. Two kinds of common constraints during maturation of immature scaffolds to active end point metabolites are macrocyclizations and hetrocyclizations. Each builds compact architectures characteristic of many high affinity, specific ligands for therapeutic targets. The chemical logic and enzymatic machinery for macrolactone and macrolactam formations are analyzed for antibiotics such as erythromycins, daptomycin, polymyxins, and vancomycin...
July 11, 2018: ACS Infectious Diseases
Chowdhury Raihan Bikash, Sally R Hamry, Yftah Tal-Gan
Streptococcus mutans is a Gram-positive human pathogen that is one of the major contributors to dental caries, a condition with an economic cost of over $100 billion per year in the United States. S. mutans secretes a 21-amino-acid peptide termed the competence stimulating peptide (21-CSP) to assess its population density in a process termed quorum sensing (QS) and to initiate a variety of phenotypes such as biofilm formation and bacteriocin production. 21-CSP is processed by a membrane bound protease SepM into active 18-CSP, which then binds to the ComD receptor...
July 10, 2018: ACS Infectious Diseases
Manish Nepal, Mohamed Mohamed, Reena Blade, Hassan Eldesouky, Tiffany Anderson, Mohamed N Seleem, Jean Chmielewski
A number of pathogenic bacteria reproduce inside mammalian cells and are thus inaccessible to many antimicrobial drugs. Herein, we present a facile method to a focused library of antibacterial agents known as cationic amphiphilic polyproline helices (CAPHs). We identified three CAPHs from the library with superior cell penetration within macrophages and excellent antibacterial action against both Gram-positive and Gram-negative bacteria. These cell-penetrating antibacterial CAPHs have specific sub-cellular localizations that allow for targeting of pathogenic bacteria at their intracellular niches, a unique feature that promotes the successful clearance of intracellular pathogens (Salmonella, Shigella and Listeria) residing within macrophages...
July 6, 2018: ACS Infectious Diseases
Jing Qiao, Max Purro, Zhi Liu, May P Xiong
Iron plays a critical role in bacterial infections and is especially critical for supporting biofilm formation. Until recently, Fe(III) was assumed to be the most relevant form of iron to chelate in therapeutic antimicrobial strategies due to its natural abundance under normal oxygen and physiologic conditions. Recent clinical data obtained from cystic fibrosis (CF) patients found that there is actually quite an abundance of Fe(II) present in sputum and that there exists a significant relationship between sputum Fe(II) concentration and severity of the disease...
July 5, 2018: ACS Infectious Diseases
Christian Adam Luong Esperitu, Christine Aubrey C Justo, Miriam Jauset-Rubio, Marketa Svobodova, Abdulaziz Saleh Omar Bashammakh, Abdulrahman Obaid Al-Youbi, Windell Rivera, Analiza Rollon, Ciara K O' Sullivan
Trichomoniasis, caused by Trichomonas vaginalis (T. vaginalis), is the leading non-viral sexually transmitted infection worldwide. We report the selection of a DNA aptamer against a T. vaginalis adhesion protein, AP65, using a microtitre plate-based in vitro combinatorial chemistry process termed systematic evolution of ligands by exponential enrichment (SELEX). The enriched library pool was sequenced by next generation sequencing and several aptamer candidates with high affinity and specificity were identified...
July 4, 2018: ACS Infectious Diseases
Silvia Acosta-Gutierrez, Luana Ferrara, Monisha Pathania, Muriel Masi, Jiajun Wang, Igor Bodrenko, Michael Zahn, Mathias Winterhalter, Robert A Stavenger, Jean-Marie Pages, James H Naismith, Bert van den Berg, Malcolm Page, Matteo Ceccarelli
Small, hydrophilic molecules, including most important antibiotics in clinical use, cross the Gram-negative outer membrane through the water-filled channels provided by porins. We have determined the X-ray crystal structures of the principal general porins from three species of Enterobacteriaceae, namely Enterobacter aerogenes, Enterobacter cloacae and Klebsiella pneumoniae and determined their antibiotic permeabilities as well as those of the orthologues from Escherichia coli. Starting from the structure of the porins and molecules we propose a physical mechanism underlying transport and condense it in a computationally efficient scoring function...
July 2, 2018: ACS Infectious Diseases
Ramkumar Iyer, Zhengqi Ye, Annette Ferrari, Leonard Duncan, M Angela Tanudra, Hong Tsao, Tiansheng Wang, Hong Gao, Christopher L Brummel, Alice L Erwin
A general method for determining bacterial uptake of compounds independent of antibacterial activity would be a valuable tool in antibacterial drug discovery. LC-MS/MS assays have been described, but it has not been shown whether the data can be used directly to inform medicinal chemistry. We describe the evaluation of an LC-MS/MS assay measuring association of compounds with bacteria, using a set of over a hundred compounds (inhibitors of NAD-dependent DNA ligase, LigA) for which in-vitro potency and antibacterial activity had been determined...
June 30, 2018: ACS Infectious Diseases
Dawei Xu, Weike Chen, Yuto J Tobin-Miyaji, Carolyn R Sturge, Su Yang, Brendan Elmore, Anju Singh, Christine Pybus, David Greenberg, Timothy J Sellati, Wei Qiang, He Dong
The discovery of AMPs has brought tremendous promise and opportunities to overcome the prevalence of bacterial resistance to commonly used antibiotics. However, their widespread use and translation into clinical application is hampered by the moderate to severe hemolytic activity and cytotoxicity. Here we presented and validated a supramolecular platform for the construction of hemo- and cytocompatible AMP-based nanomaterials, termed Self-Assembling Antimicrobial Nanofibers (SAANs). SAANs, the "nucleus" of our antimicrobial therapeutic platform, are supramolecular assemblies of de novo designed AMPs that undergo programmed self-assembly into nanostructured fibers to "punch holes" in the bacterial membrane, thus killing the bacterial pathogen...
June 27, 2018: ACS Infectious Diseases
Uday S Ganapathy, Lu Bai, Linpeng Wei, Kathryn A Eckartt, Clarissa M Lett, Mary L Previti, Isaac S Carrico, Jessica C Seeliger
No abstract text is available yet for this article.
June 25, 2018: ACS Infectious Diseases
Jin Hu, Junjun Cheng, Liudi Tang, Zhanying Hu, Yue Luo, Yuhuan Li, Tianlun Zhou, Jinhong Chang, Ju-Tao Guo
Hepatitis B virus (HBV) has infected one-third of world population, and 240 million people are chronic carriers, to whom a curative therapy is still not available. Similar to other viruses, persistent HBV infection relies on the virus to exploit host cell functions to support its replication and efficiently evade host innate and adaptive antiviral immunity. Understanding HBV replication and concomitant host cell interactions is thus instrumental for development of therapeutics to disrupt the virus-host interactions critical for its persistence and cure chronic hepatitis B...
June 25, 2018: ACS Infectious Diseases
Bradley M Minrovic, David Jung, Roberta J Melander, Christian Melander
Antibiotic resistance has become increasingly prevalent over the past few decades, and this combined with a dearth in the development of new classes of antibiotics to treat multidrug resistant Gram-negative infections has led to a significant global health problem and the increased usage of colistin as the last resort antibiotic. Colistin, however, presents dose dependent toxicity in the clinic. One potential approach to combatting this problem is the use of an antibiotic adjuvant, a compound that is nontoxic to the bacteria that enhances the potency of colistin and ultimately allows for reducing dosing...
June 25, 2018: ACS Infectious Diseases
Oscar D Ayala, Catherine A Wakeman, Isaac J Pence, Jennifer A Gaddy, James C Slaughter, Eric P Skaar, Anita Mahadevan-Jansen
Staphylococcus aureus ( S. aureus) is a leading cause of hospital-acquired infections, such as bacteremia, pneumonia, and endocarditis. Treatment of these infections can be challenging since strains of S. aureus, such as methicillin-resistant S. aureus (MRSA), have evolved resistance to antimicrobials. Current methods to identify infectious agents in hospital environments often rely on time-consuming, multistep culturing techniques to distinguish problematic strains (i.e., antimicrobial resistant variants) of a particular bacterial species...
June 25, 2018: ACS Infectious Diseases
Oleksandra Pashchenko, Tyler Shelby, Tuhina Banerjee, Santimukul Santra
Each year, infectious diseases are responsible for millions of deaths, most of which occur in the rural areas of developing countries. Many of the infectious disease diagnostic tools used today require a great deal of time, a laboratory setting, and trained personnel. Due to this, the need for effective point-of-care (POC) diagnostic tools is greatly increasing with an emphasis on affordability, portability, sensitivity, specificity, timeliness, and ease of use. In this Review, we discuss the various diagnostic modalities that have been utilized toward this end and are being further developed to create POC diagnostic technologies, and we focus on potential effectiveness in resource-limited settings...
June 18, 2018: ACS Infectious Diseases
Benjamin Spangler, Dustin Dovala, William S Sawyer, Katherine V Thompson, David A Six, Folkert Reck, Brian Y Feng
The Gram-negative cell envelope presents a formidable barrier to xenobiotics, and achieving sufficient compound exposure inside the cell is a key challenge for the discovery of new antibiotics. To provide insight on the molecular determinants governing compound exposure in Gram-negative bacteria, we developed a methodology leveraging a cyclooctyne-based bioorthogonal probe to assess compartment-specific compound exposure. This probe can be selectively localized to the periplasmic or cytoplasmic compartments of Gram-negative bacteria...
June 15, 2018: ACS Infectious Diseases
Stephanie M Bester, Courtney M Daczkowski, Kay S Faaberg, Scott D Pegan
Porcine reproductive and respiratory syndrome (PRRS) is a widespread economically devastating disease caused by PRRS virus (PRRSV). First recognized in the late 1980s, PRRSV is known to undergo somatic mutations and high frequency viral recombination, which leads to many diverse viral strains. This includes differences within viral virulence factors, such as the viral ovarian tumor domain (vOTU) protease, also referred to as the papain-like protease 2. These proteases down-regulate innate immunity by deubiquitinating proteins targeted by the cell for further processing and potentially also acting against interferon-stimulated genes (ISGs)...
June 12, 2018: ACS Infectious Diseases
Appalaraju Jaggupilli, Nisha Singh, Vivianne Cruz De Jesus, Kangmin Duan, Prashen Chelikani
The 25 bitter taste receptors (T2Rs) in humans are novel players in mediating host-pathogen responses in the airways and innate immunity. The chemosensory T2Rs are expressed in different extraoral tissues and perform diverse pathophysiological roles from mediating bronchodilation to detecting bacterial infection in the airways. T2Rs were suggested to be activated by multiple bacterial quorum sensing molecules (QSMs). However, whether bacterial QSMs bind to T2Rs and the structural features on T2Rs has not yet been characterized...
June 6, 2018: ACS Infectious Diseases
Krista M Giglio, Colleen E Keohane, Paul V Stodghill, Andrew D Steele, Christian Fetzer, Stephan A Sieber, Melanie J Filiatrault, William M Wuest
Promysalin, a secondary metabolite produced by P. putida RW10S1, is a narrow-spectrum antibiotic that targets P. aeruginosa over other Pseudomonas spp. P. putida KT2440, a nonproducing strain, displays increased swarming motility and decreased pyoverdine production in the presence of exogenous promysalin. Herein, proteomic and transcriptomic experiments were used to provide insight about how promysalin elicits responses in PPKT2440 and rationalize its species selectivity. RNA-sequencing results suggest that promysalin affects PPKT2440 by (1) increasing swarming in a flagella-independent manner; (2) causing cells to behave as if they were experiencing an iron-deficient environment, and (3) shifting metabolism away from glucose conversion to pyruvate via the Entner-Doudoroff pathway...
June 5, 2018: ACS Infectious Diseases
Ania Bogoslowski, Paul Kubes
Lymph nodes have been studied for decades as the main site of the adaptive immune response. In this Viewpoint, we outline how the lymph nodes have another less appreciated function as an active innate barrier. Lymph nodes drain lymphatic fluid from tissues that are exposed to the external environment, such as the skin, lung, or gut. Pathogens that travel through lymphatics should be able to enter the circulation, if it were not for the strategic localization of lymph nodes along lymphatics which prevent systemic access...
June 1, 2018: ACS Infectious Diseases
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