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ACS Infectious Diseases

Aiguo Xia, Jundong Han, Zhenyu Jin, Lei Ni, Shuai Yang, Fan Jin
We present a method capable of detecting single slow-growing and growth-arrested cells in a bacterial culture composed of physiologically and phenotypically different cells. Unlike the use of transcriptional reporters to gauge the metabolic activities in cells, here, we fuse two different fluorescent proteins with distinctive maturation rates to construct a timer to directly determine the growth rate of single Pseudomonas aeruginosa cells. We demonstrate that the dual-color fluorescent timer can indicate the slow-growing and growth-arrested cells from bacterial cultures in the presence of various environmental stresses, including nutrient starvation or antibiotic treatments, which greatly expand the methods for detecting and isolating persister cells...
September 14, 2018: ACS Infectious Diseases
Andrew B Hill, Marie Beitelshees, Roozbeh Nayerhoda, Blaine A Pfeifer, Charles H Jones
We detail the development of a next-generation Streptococcus pneumoniae liposomal encapsulation of polysaccharides (LEPS) vaccine, with design characteristics geared toward best-in-class efficacy. The first generation LEPS vaccine, which contained 20 encapsulated pneumococcal capsular polysaccharides (CPSs) and two surface-displayed virulence-associated proteins (GlpO and PncO), enabling prophylactic potency against 70+ serotypes of Streptococcus pneumoniae (the causative agent of pneumococcal disease), was rationally redesigned for advanced clinical readiness and best-in-class coverage...
September 14, 2018: ACS Infectious Diseases
Ana V Morales-de-Echegaray, Thora R Maltais, Lu Lin, Waleed Younis, Naveen R Kadasala, Mohamed N Seleem, Alexander Wei
Antimicrobial photodynamic therapy (aPDT) is a promising method for the topical treatment of drug-resistant staphylococcal infections and can be further improved by identifying mechanisms that increase the specificity of photosensitizer uptake by bacteria. Here we show that Ga(III)-protoporphyrin IX chloride (Ga-PpIX), a fluorescent hemin analog with previously undisclosed photosensitizing properties, can be taken up within seconds by Staphylococcus aureus including multidrug-resistant strains such as MRSA...
September 13, 2018: ACS Infectious Diseases
Michael Phan, Margaret F Watson, Tommy Alain, Jean-Simon Diallo
Over the past 20 years there has been a dramatic expansion in the testing of oncolytic viruses (OVs) for the treatment of cancer. OVs are unique biotherapeutics that induce multimodal responses toward tumors, from direct cytopathic effects on cancer cells, to tumor associated blood vessel disruption, and ultimately potent stimulation of anti-tumor immune activation. These agents are highly targeted and can be efficacious as cancer treatments resulting in some patients experiencing complete tumor regression and even cures from OV monotherapy...
September 12, 2018: ACS Infectious Diseases
Marta Fratini, Tina Wiegand, Charlotta Funaya, Zhongxiang Jiang, Pranav N M Shah, Joachim Spatz, Elisabetta A Cavalcanti-Adam, Steeve Boulant
Clathrin-mediated endocytosis (CME) is an important entry pathway for viruses. Here, we applied click chemistry to covalently immobilize reovirus on surfaces to study CME during early host-pathogen interactions. To uncouple chemical and physical properties of viruses and determine their impact on CME initiation, we used the same strategy to covalently immobilize nanoparticles of different sizes. Using fluorescence live microscopy and electron microscopy, we confirmed that clathrin recruitment depends on particle size and discovered that the maturation into clathrin-coated vesicles (CCVs) is independent from cargo internalization...
September 10, 2018: ACS Infectious Diseases
Andrew Vaillant
Nucleic acid polymers (NAPs) are broad spectrum antiviral agents whose antiviral activity in HBV infection is derived from their ability to block the release of HBsAg. This pharmacological activity effectively blocks replenishment of HBsAg in the circulation, allowing host mediated clearance. This effect has important clinical significance as the clearance of circulating HBsAg dramatically potentiates the ability of immunotherapies to restore functional control of HBV infection which persists after antiviral therapy is removed...
September 10, 2018: ACS Infectious Diseases
Paul W Smith, Fabio Zuccotto, Robert H Bates, Maria Santos Martinez-Martinez, Kevin D Read, Caroline Peet, Ola Epemolu
β-Lactams represent perhaps the most important class of antibiotics yet discovered. However, despite many years of active research, none of the currently approved drugs in this class combine oral activity with long duration of action. Recent developments suggest that new β-lactam antibiotics with such a profile would have utility in the treatment of tuberculosis. Consequently, the historical β-lactam pharmacokinetic data have been compiled and analyzed to identify possible directions and drug discovery strategies aimed toward new β-lactam antibiotics with this profile...
September 10, 2018: ACS Infectious Diseases
M Daben J Libardo, Cesar de la Fuente-Nuñez, Kushi Anand, Gopinath Krishnamoorthy, Peggy Kaiser, Stephanie C Pringle, Christopher Dietz, Scott Pierce, Michael B Smith, Amy Barczak, Stefan H E Kaufmann, Amit Singh, Alfredo M Angeles-Boza
Copper (Cu) ions are critical in controlling bacterial infections, and successful pathogens like Mycobacterium tuberculosis (Mtb) possess multiple Cu resistance mechanisms. We report, as proof of concept, that a novel Cu hypersensitivity phenotype can be generated in mycobacteria, including Mtb, through a peptide, DAB-10, that is able to form reactive oxygen species (ROS) following Cu-binding. DAB-10 induces intramycobacterial oxidative stress in a Cu-dependent manner in vitro and during infection. DAB-10 penetrates murine macrophages and encounters intracellular mycobacteria...
September 6, 2018: ACS Infectious Diseases
Anna Katharina Schuh, Mahsa Rahbari, Kim C Heimsch, Franziska Mohring, Stanislaw J Gabryszewski, Stine Weder, Kathrin Buchholz, Stefan Rahlfs, David A Fidock, Katja Becker
Studying redox metabolism in malaria parasites is of great interest for understanding parasite biology, parasite-host interactions, and mechanisms of drug action. Genetically encoded fluorescent redox sensors have recently been described as powerful tools for determining the glutathione-dependent redox potential in living parasites. In the present study, we genomically integrated and expressed the ratiometric redox sensors hGrx1-roGFP2 (human glutaredoxin 1 fused to reduction-oxidation sensitive green fluorescent protein) and sfroGFP2 (superfolder roGFP2) in the cytosol of NF54- attB blood-stage Plasmodium falciparum parasites...
September 6, 2018: ACS Infectious Diseases
Sujeethraj Koppolu, Linlin Wang, Ayushi Mathur, Jayeshwar A Nigam, Charlene S Dezzutti, Charles Isaacs, Leslie Meyn, Katherine E Bunge, Bernard J Moncla, Sharon L Hillier, Lisa C Rohan, Lara K Mahal
Glycosylated proteins (i.e. mucins, IgG) are important mediators of innate antiviral immunity in the vagina, however our current knowledge of the role that glycan themselves play in genital immunity is relatively low. Herein we evaluate the relationship between innate antiviral immunity and glycomic composition in cervicovaginal lavage fluid (CVL) collected as part of a phase-I clinical trial testing the impact of two distinct formulations of the antiretroviral drug dapivirine. Using lectin microarray technology, we discovered that formulation (hydrogel- versus film-based delivery) impacted the CVL glycome, with hydrogel formulations inducing more changes, including a loss of high mannose...
September 5, 2018: ACS Infectious Diseases
Erin V McConnell, Igor Bruzual, Sovitj Pou, Rolf Winter, Rozalia A Dodean, Martin J Smilkstein, Alina Krollenbrock, Aaron Nilsen, Lev N Zakharov, Michael K Riscoe, J Stone Doggett
Cytochrome bc1 inhibitors have been broadly studied as human and veterinary medicines and agricultural fungicides. For the most part, cytochrome bc1 inhibitors compete with ubiquinol at the ubiquinol oxidation (Qo) site or with ubiquinone at the quinone reduction (Qi) site. 4(1 H)-Quinolones with 3-position substituents may inhibit either site based on quinolone ring substituents. 4(1 H)-Quinolones that inhibit the Qi site are highly effective against toxoplasmosis, malaria, and babesiosis and do not inhibit human cytochrome bc1 ...
August 30, 2018: ACS Infectious Diseases
Wooseong Kim, Andrew D Steele, Wenpeng Zhu, Erika E Csatary, Nico Fricke, Madeline M Dekarske, Elamparithi Jayamani, Wen Pan, Bumsup Kwon, Isabelle F Sinitsa, Jake L Rosen, Annie L Conery, Beth Burgwyn Fuchs, Petia M Vlahovska, Frederick M Ausubel, Huajian Gao, William M Wuest, Eleftherios Mylonakis
Conventional antibiotics are not effective in treating infections caused by drug-resistant or persistent nongrowing bacteria, creating a dire need for the development of new antibiotics. We report that the small molecule nTZDpa, previously characterized as a nonthiazolidinedione peroxisome proliferator-activated receptor gamma partial agonist, kills both growing and persistent Staphylococcus aureus cells by lipid bilayer disruption. S. aureus exhibited no detectable development of resistance to nTZDpa, and the compound acted synergistically with aminoglycosides...
August 28, 2018: ACS Infectious Diseases
Joshua B Radke, Kimberly L Carey, Subrata Shaw, Shailesh R Metkar, Carol Mulrooney, Jennifer P Gale, Joshua A Bittker, Robert Hilgraf, Eamon Comer, Stuart L Schreiber, Herbert W Virgin, Jose R Perez, L David Sibley
Toxoplasma gondii is an obligate intracellular parasite capable of causing severe disease due to congenital infection and in patients with compromised immune systems. Control of infection is dependent on a robust Th1 type immune response including production of interferon gamma (IFN-γ), which is essential for control. IFN-γ activates a variety of antimicrobial mechanisms in host cells, which are then able to control intracellular parasites such as T. gondii. Despite the effectiveness of these pathways in controlling acute infection, the immune system is unable to eradicate chronic infections that can persist for life...
August 28, 2018: ACS Infectious Diseases
Ryan Shirey, Daniel Globisch, Lisa M Eubanks, Mark S Hixon, Kim D Janda
The parasitic disease onchocerciasis is the second leading cause of preventable blindness, afflicting more than 18 million people worldwide. Despite an available treatment, ivermectin, and control efforts by the World Health Organization, onchocerciasis remains a burden in many regions. With an estimated 120 million people living in areas at risk of infection, efforts are now shifting from prevention to surveillance and elimination. The lack of a robust, point-of-care diagnostic for an active Onchocerca infection has been a limiting factor in these efforts...
August 24, 2018: ACS Infectious Diseases
Aileen Rubio, Michael J Pucci, Akash Jain
Carbapenems are potent antibacterials with broad-spectrum activity. However, poor oral absorption generally confines this important drug class to in-hospital use by intravenous (IV) administration. The continued rise in drug resistant pathogens creates a need for alternative oral therapies with broad-spectrum activity. SPR994 is a novel formulation of the orally bioavailable pivoxil prodrug of SPR859 (tebipenem) and is being developed as the first oral carbapenem for treatment of complicated urinary tract infections (cUTIs) in adults...
August 17, 2018: ACS Infectious Diseases
Zhuo Zhang, Alvaro A Ordonez, Hui Wang, Yong Li, Kayla R Gogarty, Edward A Weinstein, Fereidoon Daryaee, Jonathan Merino, Grace E Yoon, Alvin S Kalinda, Ronnie C Mease, James N Iuliano, Peter M Smith-Jones, Sanjay K Jain, Peter J Tonge
Staphylococcus aureus is the leading cause of life-threatening infections, frequently originating from unknown or deep-seated foci. Source control and institution of appropriate antibiotics remain challenges, especially with infections due to methicillin-resistant S. aureus (MRSA). In this study, we developed a radiofluorinated analog of para-aminobenzoic acid (2-[18 F]F-PABA) and demonstrate that it is an efficient alternative substrate for the S. aureus dihydropteroate synthase (DHPS). 2-[18 F]F-PABA rapidly accumulated in vitro within laboratory and clinical (including MRSA) strains of S...
August 17, 2018: ACS Infectious Diseases
Silvia Acosta-Gutiérrez, Luana Ferrara, Monisha Pathania, Muriel Masi, Jiajun Wang, Igor Bodrenko, Michael Zahn, Mathias Winterhalter, Robert A Stavenger, Jean-Marie Pagès, James H Naismith, Bert van den Berg, Malcolm G P 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...
August 17, 2018: ACS Infectious Diseases
Adam J Schaenzer, Nathan Wlodarchak, David H Drewry, William J Zuercher, Warren E Rose, Carla A Ferrer, John-Demian Sauer, Rob Striker
As antibiotic resistance rises, there is a need for strategies such as antibiotic adjuvants to conserve already-established antibiotics. A family of bacterial kinases known as the penicillin-binding-protein and serine/threonine kinase-associated (PASTA) kinases has attracted attention as targets for antibiotic adjuvants for β-lactams. Here, we report that the pyrazolopyridazine GW779439X sensitizes methicillin-resistant Staphylococcus aureus (MRSA) to various β-lactams through inhibition of the PASTA kinase Stk1...
August 15, 2018: ACS Infectious Diseases
Manuka Ghosh, Yun-Ming Lin, Patricia A Miller, Ute Möllmann, William C Boggess, Marvin J Miller
Development of resistance to antibiotics is a major medical problem. One approach to extending the utility of our limited antibiotic arsenal is to repurpose antibiotics by altering their bacterial selectivity. Many antibiotics that are used to treat infections caused by Gram-positive bacteria might be made effective against Gram-negative bacterial infections, if they could circumvent permeability barriers and antibiotic deactivation processes associated with Gram-negative bacteria. Herein, we report that covalent attachment of the normally Gram-positive-only antibiotic, daptomycin, with iron sequestering siderophore mimetics that are recognized by Gram-negative bacteria, provides conjugates that are active against virulent strains of Acinetobacter baumannii, including carbapenemase and cephalosporinase producers...
August 9, 2018: ACS Infectious Diseases
Zhi-Chen Wu, Nicholas A Isley, Dale L Boger
A series of vancomycin derivatives alkylated at the N-terminus amine were synthesized, including those that contain quaternary trimethylammonium salts either directly at the terminal amine site or with an intervening three-carbon spacer. The examination of their properties provides important comparisons with a C-terminus trimethylammonium salt modification that we recently found to improve the antimicrobial potency of vancomycin analogues through an added mechanism of action. The N-terminus modifications disclosed herein were well-tolerated, minimally altering model ligand binding affinities (d-Ala-d-Ala) and antimicrobial activity, but did not induce membrane permeabilization that was observed with a similar C-terminus modification...
August 8, 2018: ACS Infectious Diseases
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