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ACS Infectious Diseases

Adriely Goes, Gregor Fuhrmann
Biogenic and biomimetic therapeutics are a relatively new class of systems that are of physiological origin and/or take advantage of natural pathways, or aim at mimicking these to improve selective interaction with target tissue. The number of biogenic and bioengineered avenues for drug therapy and diagnostics has multiplied over the past years for many applications, indicating the high expectations associated with this biological route. Nevertheless, the use of "bio"-related approaches for treating or diagnosing infectious diseases is still rare...
March 19, 2018: ACS Infectious Diseases
Maria J Gonzalez-Moa, Bieke Van Dorst, Ole Lagatie, Ann Verheyen, Lieven Stuyver, Marco A Biamonte
Three O. volvulus immunogenic peptide sequences recently discovered by peptide microarray were adapted to a lateral flow assay (LFA). The LFA employs gold nanoshells as novel high-contrast reporter nanoparticles and detects a serological response against the 3 peptides, found in OvOC9384, OvOC198, and OvOC5528, respectively. When tested on 118 sera from O. volvulus infected patients and 208 control sera, the LFA was 90, 63, and 98% sensitive for each peptide, respectively, and 99-100% specific vs. samples from healthy volunteers...
March 16, 2018: ACS Infectious Diseases
Pamela Orjuela-Sanchez, Zaira Hellen Villa, Marta Moreno, Carlos Tong-Rios, Stephan Meister, Gregory M LaMonte, Brice Campo, Joseph M Vinetz, Elizabeth A Winzeler
To develop new drugs and vaccines for malaria elimination, it will be necessary to discover biological interventions, including small molecules that act against Plasmodium vivax exoerythrocytic forms. However, a robust in vitro culture system for P. vivax is still lacking. Thus, to study exoerythrocytic forms, researchers must have simultaneous access to fresh, temperature-controlled patient blood samples, as well as an anopheline mosquito colony. In addition, researchers must rely on native mosquito species to avoid introducing a potentially dangerous invasive species into a malaria-endemic region...
March 15, 2018: ACS Infectious Diseases
Wonsik Lee, Truc Do, Ge Zhang, Daniel Kahne, Timothy C Meredith, Suzanne Walker
Targeted modification of bacterial chromosomes is necessary to understand new drug targets, investigate virulence factors, elucidate cell physiology, and validate results of -omics-based approaches. For some bacteria, reverse genetics remains a major bottleneck to progress in research. Here we describe a compound-centric strategy that combines new negative selection markers with known positive selection markers to achieve simple, efficient one-step genome engineering of bacterial chromosomes. The method was inspired by the observation that certain non-essential metabolic pathways contain essential late steps, suggesting that antibiotics targeting a late step can be used to select for the absence of genes that control flux into the pathway...
March 13, 2018: ACS Infectious Diseases
Dinakaran Murugesan, Peter C Ray, Tracy Bayliss, Gareth A Prosser, Justin R Harrison, Kirsteen Green, Candice Soares de Melo, Tzu-Shean Feng, Leslie J Street, Kelly Chibale, Digby F Warner, Valerie Mizrahi, Ola Epemolu, Paul Scullion, Lucy Ellis, Jennifer Riley, Yoko Shishikura, Liam Ferguson, Maria Osuna-Cabello, Kevin D Read, Simon R Green, Dirk A Lamprecht, Peter M Finin, Adrie J C Steyn, Thomas R Ioerger, Jim Sacchettini, Kyu Y Rhee, Kriti Arora, Clifton E Barry Iii, Paul G Wyatt, Helena Ingrid M Boshoff
Mycobacterium tuberculosis (MTb) possesses two non-proton pumping type II NADH dehydrogenase (NDH-2) enzymes which are predicted to be jointly essential for respiratory metabolism.. Furthermore, the structure of a closely related bacterial NDH-2 has been reported recently, allowing for the structure-based design of small-molecule inhibitors. Herein, we disclose MTb whole-cell structure-activity relationships (SAR) for a series of 2-mercapto-quinazolinones which target the ndh encoded NDH-2 with nanomolar potencies...
March 9, 2018: ACS Infectious Diseases
Rama Subba Rao Vidadala, Martin Golkowski, Matthew A Hulverson, Ryan Choi, Molly C McCloskey, Grant R Whitman, Wenlin Huang, Samuel L M Arnold, Lynn K Barrett, Erkang Fan, Ethan A Merritt, Wesley C Van Voorhis, Kayode K Ojo, Dustin J Maly
Selective inhibitors of Cryptosporidium Calcium-Dependent Protein Kinase 1 (CpCDPK1) based on the 1H-pyrazolo[3,4-d]pyrimidin-4-amine (pyrazolopyrimidine, PP) scaffold are effective in both in vitro and in vivo models of cryptosporidiosis. However, the search for distinct safety and pharmacokinetic (PK) properties has motivated our exploration of alternative scaffolds. Here, we describe a series of 7H-pyrrolo[2,3-d]pyrimidin-4-amine (pyrrolopyrimidine, PrP)-based analogs of PP CpCDPK1 inhibitors. Most of the PrP-based inhibitors described potently inhibit the CpCDPK1 enzyme, demonstrate no toxicity against mammalian cells, and block proliferation of the C...
March 9, 2018: ACS Infectious Diseases
Harshana S De Silva Feelixge, Daniel Stone, Pavitra Roychoudhury, Martine Aubert, Keith R Jerome
Chronic viral infections remain a major public health issue affecting millions of people worldwide. Highly active antiviral treatments have significantly improved prognosis and infection-related morbidity and mortality, but have failed to eliminate persistent viral forms. Therefore, new strategies to either eradicate or control these viral reservoirs are paramount to allow patients to stop antiretroviral therapy and realize a cure. Viral genome disruption based on gene editing by programmable endonucleases is one promising curative gene therapy approach...
March 9, 2018: ACS Infectious Diseases
Sabrina S Schatzman, Valeria C Culotta
Superoxide anion radical is generated as a natural byproduct of aerobic metabolism, but is also produced as part of the oxidative burst of the innate immune response design to kill pathogens. In living systems, superoxide is largely managed through superoxide dismutases (SODs), families of metalloenzymes that use Fe, Mn, Ni or Cu cofactors to catalyze the disproportionation of superoxide to oxygen and hydrogen peroxide. Given the bursts of superoxide faced by microbial pathogens, it comes as no surprise that SOD enzymes play important roles in microbial survival and virulence...
March 8, 2018: ACS Infectious Diseases
Geneviève F Desrochers, Christina Cornacchia, Craig S McKay, John Paul Pezacki
Protein-protein interactions are integral to host-virus inter-actions and can contribute significantly to enzyme regula-tion by changing the localization of both host and viral en-zymes within the cell, inducing conformational change rele-vant to enzyme activity, or recruiting other additional pro-teins to form functional complexes. Identifying the interac-tors of active enzymes using an activity-based protein profil-ing probe has allowed us to characterize both normal en-zyme activation mechanisms, and the manner by which these are mechanisms are hijacked and altered by the hepati-tis C virus (HCV)...
March 6, 2018: ACS Infectious Diseases
Andreas M Kany, Asfandyar Sikandar, Jörg Haupenthal, Samir Yahiaoui, Christine K Maurer, Ewgenij Proschak, Jesko Köhnke, Rolf W Hartmann
The increasing emergence of antibiotic resistance necessitates the development of anti-infectives with novel modes of action. Targeting bacterial virulence is considered a promising approach to develop novel antibiotics with reduced selection pressure. The extracellular collagenase elastase (LasB) plays a pivotal role in the infection process of Pseudomonas aeruginosa and therefore represents an attractive antivirulence target. Mercaptoacetamide-based thiols have been reported to inhibit LasB as well as collagenases from clostridia and bacillus species...
March 6, 2018: ACS Infectious Diseases
Banhi Biswas, Pooja Kumari, Perumal Vivekanandan
Packaging signals (pac1 and pac2) of human herpesviruses (HHVs) that contain GC-rich elements are essential for cleavage and packaging of the virus. Here, we report the presence of putative G-quadruplex sequences (PQSs) in the packaging signal (pac1) of all HHVs. Importantly, the residues critical for the formation of G-quadruplex structures were highly conserved as compared to those not critical for the formation of this DNA secondary structure, indicating that G-quadruplexes are positively selected within pac1 in the evolution of herpesviruses...
March 1, 2018: ACS Infectious Diseases
Ruben Tommasi, Ramkumar Iyer, Alita A Miller
Our limited understanding of the molecular basis for compound entry into and efflux out of Gram-negative bacteria is now recognized as a key bottleneck for the rational discovery of novel antibacterial compounds. Traditional, large-scale biochemical or target-agnostic phenotypic antibacterial screening efforts have, as a result, not been very fruitful. A main driver of this knowledge gap has been the historical lack of predictive cellular assays, tools, and models that provide structure-activity relationships to inform optimization of compound accumulation...
February 27, 2018: ACS Infectious Diseases
Jeffrey M Grabowski, Danielle K Offerdahl, Marshall E Bloom
Each year there are more than 15 000 cases of human disease caused by infections with tick-borne viruses (TBVs). These illnesses occur worldwide and can range from very mild illness to severe encephalitis and hemorrhagic fever. Although TBVs are currently identified as neglected vector-borne pathogens and receive less attention than mosquito-borne viruses, TBVs are expanding into new regions, and infection rates are increasing. Furthermore, effective vaccines, diagnostic tools, and other countermeasures are limited...
February 23, 2018: ACS Infectious Diseases
Amberlyn M Wands, Jakob Cervin, He Huang, Ye Zhang, Gyusaang Youn, Chad A Brautigam, Maria Matson Dzebo, Per Björklund, Ville Wallenius, Danielle K Bright, Clay S Bennett, Pernilla Wittung-Stafshede, Nicole S Sampson, Ulf Yrlid, Jennifer J Kohler
Cholera toxin (CT) enters host intestinal epithelia cells, and its retrograde transport to the cytosol results in the massive loss of fluids and electrolytes associated with severe dehydration. To initiate this intoxication process, the B subunit of CT (CTB) first binds to a cell surface receptor displayed on the apical surface of the intestinal epithelia. While the monosialoganglioside GM1 is widely accepted to be the sole receptor for CT, intestinal epithelial cell lines also utilize fucosylated glycan epitopes on glycoproteins to facilitate cell surface binding and endocytic uptake of the toxin...
February 22, 2018: ACS Infectious Diseases
Ana Negri, Prisca Javidnia, Ran Mu, Xiaojie Zhang, Jeremie Vendome, Ben Gold, Julia Roberts, Dipti Barman, Thomas Ioerger, James C Sacchettini, Xiuju Jiang, Kristin Burns-Huang, Thulasi Warrier, Yan Ling, J David Warren, Deena A Oren, Thijs Beuming, Hongyao Wang, Jie Wu, Haitao Li, Kyu Y Rhee, Carl F Nathan, Gang Liu, Selin Somersan-Karakaya
The success of Mycobacterium tuberculosis (Mtb) as a pathogen depends on the redundant and complex mechanisms it has evolved for resisting nitrosative and oxidative stresses inflicted by host immunity. Improving our understanding of these defense pathways can reveal vulnerable points in Mtb pathogenesis. In this study, we combined genetic, structural, computational, biochemical, and biophysical approaches to identify a novel enzyme class represented by Rv2466c. We show that Rv2466c is a mycothiol-dependent nitroreductase of Mtb and can reduce the nitro group of a novel mycobactericidal compound using mycothiol as a cofactor...
February 21, 2018: ACS Infectious Diseases
Tania J Lupoli, Julien Vaubourgeix, Kristin Burns-Huang, Ben Gold
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains one of the world's deadliest infectious diseases and urgently requires new antibiotics to treat drug-resistant strains and to decrease the duration of therapy. During infection, Mtb encounters numerous stresses associated with host immunity, including hypoxia, reactive oxygen and nitrogen species, mild acidity, nutrient starvation, and metal sequestration and intoxication. The Mtb proteostasis network, composed of chaperones, proteases, and a eukaryotic-like proteasome, provides protection from stresses and chemistries of host immunity by maintaining the integrity of the mycobacterial proteome...
February 21, 2018: ACS Infectious Diseases
Marta Moreno, Carlos Tong-Rios, Pamela Orjuela-Sanchez, Gabriel Carrasco-Escobar, Brice Campo, Dionicia Gamboa, Elizabeth A Winzeler, Joseph M Vinetz
In vitro culture of Plasmodium vivax liver stages underlies key understandings of the fundamental biology of this parasite, particularly the latent, hyponozoite stage, towards drug and vaccine development. Here we report systematic production of P. vivax sporozoites in colonized Anopheles darlingi mosquitoes in the Peruvian Amazon. Human subject-derived P. vivax-infected blood was fed to A. darlingi females using standard membrane feedings assays. Optimizing A. darlingi infection and sporozoite production included replacement of infected patient donor serum with naïve donor serum, comparing anticoagulants in processing blood samples, addition of penicillin-streptomycin and ATP to infectious blood meals...
February 21, 2018: ACS Infectious Diseases
Madeline R Luth, Purva Gupta, Sabine Ottilie, Elizabeth A Winzeler
Although many new anti-infectives have been discovered and developed solely using phenotypic cellular screening and assay optimization, most researchers recognize that structure-guided drug design is more practical and less costly. In addition, a greater chemical space can be interrogated with structure-guided drug design. The practicality of structure-guided drug design has launched a search for the targets of compounds discovered in phenotypic screens. One method that has been used extensively in malaria parasites for target discovery and chemical validation is in vitro evolution and whole genome analysis (IVIEWGA)...
February 21, 2018: ACS Infectious Diseases
Seth M Daly, Carolyn R Sturge, Kimberly R Marshall-Batty, Christina F Felder-Scott, Raksha Jain, Bruce Geller, David Greenberg
The Burkholderia cepacia complex is a group of gram-negative bacteria that are opportunistic pathogens in immunocompromised individuals, such as those with cystic fibrosis (CF) or chronic granulomatous disease (CGD). Burkholderia are intrinsically resistant to many antibiotics and the lack of antibiotic development necessitates novel therapeutics. Peptide-conjugated phosphorodiamidate morpholino oligomers are antisense molecules that inhibit bacterial mRNA translation. Targeting of PPMOs to the gene acpP, which is essential for membrane synthesis, lead to defects in the membrane and ultimately bactericidal activity...
February 20, 2018: ACS Infectious Diseases
Gerry Sann M Rivera, Catherine Rose Beamish, Timothy Adam Wencewicz
Siderophores are a structurally diverse class of natural products common to most bacteria and fungi as iron(III)-chelating ligands. Siderophores, including trihydroxamate ferrioxamines, are used clinically to treat iron overload diseases and show promising activity against many other iron-related human diseases. Here we present a new method for the isolation of ferrioxamine siderophores from complex mixtures using affinity chromatography based on resin-immobilized FhuD2, a siderophore-binding protein (SBP) from Staphylococcus aureus...
February 20, 2018: ACS Infectious Diseases
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