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ACS Infectious Diseases

Eric C Abenojar, Sameera Wickramasinghe, Minseon Ju, Sarika Uppaluri, Alison Klika, Jaiben George, Wael Barsoum, Salvatore J Frangiamore, Carlos A Higuera-Rueda, Anna Cristina S Samia
Bacterial biofilms are highly antibiotic resistant microbial cell associations that lead to chronic infections. Unlike free-floating planktonic bacterial cells, the biofilms are encapsulated in a hardly penetrable extracellular polymeric matrix and, thus, demand innovative approaches for treatment. Recent advancements on the development of gel-nanocomposite systems with tailored therapeutic properties provide promising routes to develop novel antimicrobial agents that can be designed to disrupt and completely eradicate preformed biofilms...
May 18, 2018: ACS Infectious Diseases
Stella Hartmann, Renae Lopez Cruz, Saleem Alameh, Chi-Lee C Ho, Amy Rabideau, Bradley L Pentelute, Kenneth A Bradley, Mikhail Martchenko
Exploiting the host endocytic trafficking pathway is a common mechanism by which bacterial exotoxins gain entry to exert virulent effects upon the host cells. A previous study identified a small-molecule, 1-(2,6-dimethyl-1-piperidinyl)-3-[(2-isopropyl-5-methylcyclohexyl)oxy]-2-propanol, that blocks the process of anthrax lethal toxin (LT) cytotoxicity. Here, we report the characterization of the bioactivity of this compound, which we named RC1. We found that RC1 protected host cells independently of LT concentration and also blocked intoxication by other bacterial exotoxins, suggesting that the target of the compound is a host factor...
May 18, 2018: ACS Infectious Diseases
Lori L Burrows
Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen, designated by the World Health Organization as a critical priority for development of new therapeutics due to high levels of intrinsic and acquired antibiotic resistance. Other challenges include its versatility (it can persist in the environment and most strains are capable of causing disease in compromised hosts), robust efflux mechanisms that limit drug penetration, and the propensity to form antimicrobial-tolerant biofilms. Novel therapeutics in development to prevent or treat P...
May 17, 2018: ACS Infectious Diseases
Mark A T Blaskovich
Antimicrobial resistance is a serious threat to global health. Despite numerous initiatives designed to curb excessive and inappropriate use of antibiotics, a recent report ( Klein et al. ( 2018 ) Proc. Natl. Acad. Sci. U. S. A. , 115 , E3463 ) finds that there was a substantial increase in global antibiotic consumption by humans from 2000 to 2015 and predicts a further 200% increase by 2030. Alarmingly, much of this growth is occurring in "last-resort" antibiotics. The study excludes the extensive use of antibiotics in agriculture and aquaculture...
May 14, 2018: ACS Infectious Diseases
Sarah J Cooper, Ganesh Krishnamoorthy, David Wolloscheck, John K Walker, Valentin V Rybenkov, Jerry M Parks, Helen I Zgurskaya
The permeability barrier of Gram-negative cell envelopes is the major obstacle in the discovery and development of new antibiotics. In Gram-negative bacteria, these difficulties are exacerbated by the synergistic interaction between two biochemically distinct phenomena, the low permeability of the outer membrane (OM) and active multidrug efflux. In this study, we used Pseudomonas aeruginosa and Escherichia coli strains with controllable permeability barriers-achieved through hyperporination of the OMs and varied efflux capacities-to evaluate the contributions of each of the barriers to protection from antibacterials...
May 14, 2018: ACS Infectious Diseases
Satoru Watanabe, Jenny Guek Hong Low, Subhash G Vasudevan
At present, there are no licensed antiviral drug against dengue virus (DENV) infection. Mouse models of DENV infection have been widely used for pre-clinical evaluation of antivirals. However, only in a few instances so far have the data obtained from pre-clinical mouse model testing been associated with data from clinical studies in humans. In this review, we focus on the antiviral drugs targeting viral replication that have been tested in animals/humans, and discuss how pre-clinical drug evaluation in suitable mouse/animal models may be more fruitfully used to inform early phase clinical testing...
May 14, 2018: ACS Infectious Diseases
Florian Graef, Robert Richter, Verena Fetz, Xabier Murgia, Chiara De Rossi, Nicole Schneider-Daum, Giuseppe Allegretta, Walid A M Elgaher, Jörg Haupenthal, Martin Empting, Felix Beckmann, Mark Brönstrup, Rolf W Hartmann, Sarah Gordon, Claus-Michael Lehr
The cell envelope of Gram-negative bacteria is a formidable biological barrier, inhibiting the action of antibiotics by impeding their permeation into the intracellular environment. In-depth understanding of permeation through this barrier remains a challenge, despite its critical role in antibiotic activity. We therefore designed a divisible in vitro permeation model of the Gram-negative bacterial cell envelope, mimicking its three essential structural elements - the inner membrane, the periplasmic space as well as the outer membrane - on a Transwell® setup...
May 11, 2018: ACS Infectious Diseases
Christine M Artim, Ngoc Nhu Phan, Christopher A Alabi
In response to the urgent need for new antibiotic development strategies, antimicrobial peptides and their synthetic mimetics are being investigated as promising alternatives to traditional antibiotics. To facilitate their development into clinically viable candidates, we need to understand what molecular features and physicochemical properties are needed to induce cell death. Within the context of sequence-defined oligothioetheramides (oligoTEAs), we explore the impact of the cationic pendant group and backbone hydrophobicity on the potency and selectivity of antibacterial oligoTEAs...
May 11, 2018: ACS Infectious Diseases
Elizabeth G Gibson, Tim R Blower, Monica Cacho, Ben David Bax, James M Berger, Neil Osheroff
Tuberculosis is one of the leading causes of morbidity worldwide and the incidences of drug resistance and intolerance are prevalent. Thus, there is a desperate need for the development of new anti-tubercular drugs. Mycobacterium tuberculosis gyrase inhibitors (MGIs) are napthyridone/aminopiperidine-based drugs that display activity against M. tuberculosis cells and tuberculosis in mouse models [Blanco, D., et al. (2015) Antimicrob. Agents Chemother. 59, 1868-1875]. Genetic and mutagenesis studies suggest that gyrase, which is the target for fluoroquinolone antibacterials, is also the target for MGIs...
May 10, 2018: ACS Infectious Diseases
Eric Krueger, Shannon Hayes, En Hyung Chang, Shailagne Yutuc, Angela C Brown
The Gram-negative bacterium Aggregatibacter actinomycetemcomitans, commonly associated with localized aggressive periodontitis (LAP), secretes an RTX (repeats-in-toxin) protein leukotoxin (LtxA) that targets human white blood cells, an interaction that is driven by its recognition of the lymphocyte function-associated antigen-1 (LFA-1) integrin. In this study, we report on the inhibition of LtxA-LFA-1 binding as an anti-virulence strategy to inhibit LtxA-mediated cytotoxicity. Specifically, we designed and synthesized peptides corresponding to the reported LtxA binding domain on LFA-1 and characterized their capability to inhibit LtxA binding to LFA-1 and subsequent cytotoxic activity in human immune cells...
May 9, 2018: ACS Infectious Diseases
Charles M Voyton, Meredith T Morris, P Christine Ackroyd, James C Morris, Kenneth A Christensen
Trypanosoma brucei, which causes human African typanosomiasis (HAT), derives cellular ATP from glucose metabolism while in the mammalian host. Targeting glucose uptake or regulation in the parasite has been proposed as a potential therapeutic strategy. However, few methods have been described to identify and characterize potential inhibitors of glucose uptake and regulation. Here, we report development of a screening assay that identifies small molecule disrupters of glucose levels in the cytosol and glycosomes...
May 9, 2018: ACS Infectious Diseases
Christopher A Mutch, Alvaro A Ordonez, Hecong Qin, Matthew Parker, Lauren E Bambarger, Javier E Villanueva-Meyer, Joseph Blecha, Valerie Carroll, Celine Taglang, Robert Flavell, Renuka Sriram, Henry VanBrocklin, Oren Rosenberg, Michael A Ohliger, Sanjay K Jain, Kiel D Neumann, David M Wilson
Imaging studies are frequently used to support the clinical diagnosis of infection. These techniques include computed tomography (CT) and magnetic resonance imaging (MRI) for structural information and single photon emission computed tomography (SPECT) or positron emission tomography (PET) for metabolic data. However, frequently, there is significant overlap in the imaging appearance of infectious and noninfectious entities using these tools. To address this concern, recent approaches have targeted bacteria-specific metabolic pathways...
May 8, 2018: ACS Infectious Diseases
Nadia Peerboom, Eneas Schmidt, Edward Trybala, Stephan Block, Tomas Bergström, Hudson P Pace, Marta Bally
Discovery and development of new antiviral therapies essentially rely on two key factors: an in-depth understanding of the mechanisms involved in viral infection and the development of fast and versatile drug screening platforms. To meet those demands, we present a biosensing platform to probe virus-cell membrane interactions on a single particle level. Our method is based on the formation of supported lipid bilayers from cell membrane material. Using total internal reflection fluorescence microscopy, we report the contribution of viral and cellular components to the interaction kinetics of herpes simplex virus type 1 with the cell membrane...
May 8, 2018: ACS Infectious Diseases
Venkateswarlu Yarlagadda, Paramita Sarkar, Sandip Samaddar, Goutham Belagula Manjunath, Susweta Das Mitra, Krishnamoorthy Paramanandham, Bibek R Shome, Jayanta Haldar
New Delhi Metallo-β-lactamase-1 (NDM-1) is the major contributor to the emergence of carbapenem-resistance in Gram-negative pathogens (GNPs) and has caused many clinically available β-lactam antibiotics to become obsolete. A clinically approved inhibitor of metallo-β-lactamase (MBL) that could restore the activity of carbapenems against resistant GNPs has not yet been found, making NDM-1 a serious threat to human health. Here, we have rationally developed an inhibitor for the NDM-1 enzyme, which has the ability to penetrate the outer membrane of GNPs and inactivate the enzyme by depleting the metal ion (Zn2+) from the active site...
May 4, 2018: ACS Infectious Diseases
Rahul Tyagi, Amarendar Reddy Maddirala, Mostafa Elfawal, Chelsea Fischer, Christina Bulman, Bruce A Rosa, Xin Gao, Ryan Chugani, Mingzhou Zhou, Jon Helander, Paul Brindley, Chih-Chung Tseng, Iain R Greig, Judy Sakanari, Scott A Wildman, Raffi Aroian, James W Janetka, Makedonka Mitreva
The enormous prevalence of infections caused by parasitic nematodes worldwide, coupled to the rapid emergence of their resistance to commonly used anthelmintic drugs, presents an urgent need for the discovery of new drugs. Herein, we have identified several classes of small molecules with broad spectrum activity against these pathogens. Previously, we reported the identification of carnitine palmitoyltransferases (CPTs) as a representative class of enzymes as potential targets for metabolic chokepoint intervention that was elucidated from a combination of chemogenomic screening and experimental testing in nematodes...
May 2, 2018: ACS Infectious Diseases
Shusuke Tomoshige, David A Dik, Masaaki Akabane-Nakata, Chinedu Madukoma, Jed F Fisher, Joshua D Shrout, Shahriar Mobashery
The bulgecins are iminosaccharide secondary metabolites of the Gram-negative bacterium Paraburkholderia acidophila and inhibitors of lytic transglycosylases of bacterial cell-wall biosynthesis and remodeling. The activities of the bulgecins are intimately intertwined with the mechanism of a co-biosynthesized β-lactam antibiotic. β-Lactams inhibit the penicillin-binding proteins, enzymes also critical to cell-wall biosynthesis. The simultaneous loss of the lytic transglycosylase (by bulgecin) and penicillin-binding protein (by β-lactams) activities results in deformation of the septal cell wall, observed microscopically as a bulge preceding bacterial cell lysis...
May 1, 2018: ACS Infectious Diseases
Sivan Louzoun Zada, Keith D Green, Sanjib K Shrestha, Ido M Herzog, Sylvie Garneau-Tsodikova, Micha Fridman
Here, we describe the preparation and evaluation of α,β-unsaturated carbonyl derivatives of the bacterial translation inhibiting antibiotic chloramphenicol (CAM). Compared to the parent antibiotic, two compounds containing α,β-unsaturated ketones (1 and 4) displayed a broader spectrum of activity against a panel of Gram-positive pathogens with a minimum inhibitory concentration range of 2-32 μg/mL. Interestingly, unlike the parent CAM, these compounds do not inhibit bacterial translation. Microscopic evidence and metabolic labeling of a cell wall peptidoglycan suggested that compounds 1 and 4 caused extensive damage to the envelope of Staphylococcus aureus cells by inhibition of the early stage of cell wall peptidoglycan biosynthesis...
May 1, 2018: ACS Infectious Diseases
Uday S Ganapathy, Lu Bai, Linpeng Wei, Kathryn A Eckartt, Clarissa M Lett, Mary Lou Previti, Isaac S Carrico, Jessica C Seeliger
The study of the bacterial periplasm requires techniques with sufficient spatial resolution and sensitivity to resolve the components and processes within this subcellular compartment. Peroxidase-mediated biotinylation has enabled targeted labeling of proteins within subcellular compartments of mammalian cells. We investigated whether this methodology could be applied to the bacterial periplasm. In this study we demonstrated that peroxidase-mediated biotinylation can be performed in mycobacteria and Escherichia coli...
April 30, 2018: ACS Infectious Diseases
Amr Sonousi, Vikram A Sarpe, Margarita Brilkova, Jochen Schacht, Andrea Vasella, Erik C Böttger, David Crich
Syntheses of the 6'-N-(2-hydroxyethyl) and 1-N-(4-amino-2S-hydroxybutyryl) derivatives of the 4,6-aminoglycoside sisomicin and that of the doubly modified 1-N-(4-amino-2S-hydroxybutyryl)-6'-N-(2-hydroxyethyl) derivative known as plazomicin are reported together with their antibacterial and antiribosomal activities and selectivities. The 6'-N-(2-hydroxyethyl) modification results in a moderate increase in prokaryotic/eukaryotic ribosomal selectivity, whereas the 1-N-(4-amino-2S-hydroxybutyryl) modification has the opposite effect...
April 30, 2018: ACS Infectious Diseases
Matthew R Bockman, Curtis A Engelhart, Surendra Dawadi, Peter Larson, Divya Tiwari, David M Ferguson, Dirk Schnappinger, Courtney C Aldrich
5'-[ N-(d-biotinoyl)sulfamoyl]amino-5'-deoxyadenosine (Bio-AMS, 1) possesses selective activity against Mycobacterium tuberculosis ( Mtb) and arrests fatty acid and lipid biosynthesis through inhibition of the Mycobacterium tuberculosis biotin protein ligase ( MtBPL). Mtb develops spontaneous resistance to 1 with a frequency of at least 1 × 10-7 by overexpression of Rv3406, a type II sulfatase that enzymatically inactivates 1. In an effort to circumvent this resistance mechanism, we describe herein strategic modification of the nucleoside at the 5'-position to prevent enzymatic inactivation...
April 17, 2018: ACS Infectious Diseases
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