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Therapeutics and Prevention

  • Open Access
    The Aminoalkylindole BML-190 Negatively Regulates Chitosan Synthesis via the Cyclic AMP/Protein Kinase A1 Pathway in <span class="named-content genus-species" id="named-content-1">Cryptococcus neoformans</span>
    Research Article | Therapeutics and Prevention
    The Aminoalkylindole BML-190 Negatively Regulates Chitosan Synthesis via the Cyclic AMP/Protein Kinase A1 Pathway in Cryptococcus neoformans

    Cryptococcus neoformans is a fungal pathogen that kills ∼200,000 people every year. The cell wall is an essential organelle that protects fungi from the environment. Chitosan, the deacetylated form of chitin, has been shown to be an essential component of the cryptococcal cell wall during infection of a mammalian host. In this study, we screened a set of 480 compounds...

    Brian T. Maybruck, Woei C. Lam, Charles A. Specht, Ma. Xenia G. Ilagan, Maureen J. Donlin, Jennifer K. Lodge
  • Open Access
    A Mechanosensitive Channel Governs Lipid Flippase-Mediated Echinocandin Resistance in <span class="named-content genus-species" id="named-content-1">Cryptococcus neoformans</span>
    Editor's Pick Research Article | Therapeutics and Prevention
    A Mechanosensitive Channel Governs Lipid Flippase-Mediated Echinocandin Resistance in Cryptococcus neoformans

    Cryptococcus neoformans is the leading cause of fungal meningitis, accounting for ∼15% of HIV/AIDS-related deaths, but treatment options for cryptococcosis are limited. Echinocandins are the newest fungicidal drug class introduced but are ineffective in treating cryptococcosis. Our previous study identified the lipid flippase subunit Cdc50 as a contributor to...

    Chengjun Cao, Yina Wang, Seema Husain, Patricia Soteropoulos, Chaoyang Xue
  • Open Access
    Fluconazole Monotherapy Is a Suboptimal Option for Initial Treatment of Cryptococcal Meningitis Because of Emergence of Resistance
    Research Article | Therapeutics and Prevention
    Fluconazole Monotherapy Is a Suboptimal Option for Initial Treatment of Cryptococcal Meningitis Because of Emergence of Resistance

    Cryptococcal meningitis is a lethal disease with few treatment options. The incidence remains high and intricately linked with the HIV/AIDS epidemic. In many parts of the world, fluconazole is the only agent that is available for the initial treatment of cryptococcal meningitis despite considerable evidence that it is associated with suboptimal microbiological and clinical outcomes. Fluconazole has a fungistatic mode of action: it...

    William Hope, Neil R. H. Stone, Adam Johnson, Laura McEntee, Nicola Farrington, Anahi Santoro-Castelazo, Xuan Liu, Anita Lucaci, Margaret Hughes, Jason D. Oliver, Charles Giamberardino, Sayoki Mfinanga, Thomas S. Harrison, John R. Perfect, Tihana Bicanic
  • Open Access
    A Multicomponent Vaccine Provides Immunity against Local and Systemic Infections by Group A Streptococcus across Serotypes
    Research Article | Therapeutics and Prevention
    A Multicomponent Vaccine Provides Immunity against Local and Systemic Infections by Group A Streptococcus across Serotypes

    GAS is among the most common human pathogens and causes a wide variety of diseases, likely more than any other microorganism. The diverse clinical manifestations of GAS may be attributable to its large repertoire of virulence factors that are selectively and synergistically involved in streptococcal pathogenesis. To date, GAS vaccines have not been successful due to multiple serotypes and postinfection sequelae associated with...

    Shuai Bi, Meiyi Xu, Ya Zhou, Xinxin Xing, Adong Shen, Beinan Wang
  • Open Access
    Multidrug Resistance in <span class="named-content genus-species" id="named-content-1">Neisseria gonorrhoeae</span>: Identification of Functionally Important Residues in the MtrD Efflux Protein
    Research Article | Therapeutics and Prevention
    Multidrug Resistance in Neisseria gonorrhoeae: Identification of Functionally Important Residues in the MtrD Efflux Protein

    With over 78 million new infections globally each year, gonorrhea remains a frustratingly common infection. Continuous development and spread of antimicrobial-resistant strains of Neisseria gonorrhoeae, the causative agent of gonorrhea, have posed a serious threat to public health. One of the mechanisms in...

    Mohsen Chitsaz, Lauren Booth, Mitchell T. Blyth, Megan L. O’Mara, Melissa H. Brown
  • Open Access
    Transcriptomic Signatures Predict Regulators of Drug Synergy and Clinical Regimen Efficacy against Tuberculosis
    Research Article | Therapeutics and Prevention
    Transcriptomic Signatures Predict Regulators of Drug Synergy and Clinical Regimen Efficacy against Tuberculosis

    Multidrug combination therapy is an important strategy for treating tuberculosis, the world’s deadliest bacterial infection. Long treatment durations and growing rates of drug resistance have created an urgent need for new approaches to prioritize effective drug regimens. Hence, we developed a computational model called INDIGO-MTB that identifies synergistic drug regimens from an immense set of possible drug combinations using the...

    Shuyi Ma, Suraj Jaipalli, Jonah Larkins-Ford, Jenny Lohmiller, Bree B. Aldridge, David R. Sherman, Sriram Chandrasekaran
  • Open Access
    Preclinical Efficacy of a Lipooligosaccharide Peptide Mimic Candidate Gonococcal Vaccine
    Research Article | Therapeutics and Prevention
    Preclinical Efficacy of a Lipooligosaccharide Peptide Mimic Candidate Gonococcal Vaccine

    Neisseria gonorrhoeae has become resistant to most antibiotics. The incidence of gonorrhea is also sharply increasing. A safe and effective antigonococcal vaccine is urgently needed. Lipooligosaccharide (LOS), the most abundant outer membrane molecule, is indispensable for gonococcal pathogenesis. A glycan epitope on LOS that is recognized by monoclonal antibody (MAb...

    Sunita Gulati, Michael W. Pennington, Andrzej Czerwinski, Darrick Carter, Bo Zheng, Nancy A. Nowak, Rosane B. DeOliveira, Jutamas Shaughnessy, George W. Reed, Sanjay Ram, Peter A. Rice
  • Open Access
    Fcγ Receptors Contribute to the Antiviral Properties of Influenza Virus Neuraminidase-Specific Antibodies
    Research Article | Therapeutics and Prevention
    Fcγ Receptors Contribute to the Antiviral Properties of Influenza Virus Neuraminidase-Specific Antibodies

    There is a pressing need for next-generation influenza vaccine strategies that are better able to manage antigenic drift and the cocirculation of multiple drift variants and that consistently improve vaccine effectiveness. Influenza virus NA is a key target antigen as a component of a next-generation vaccine in the influenza field, with evidence for a role in protective immunity in humans. However, mechanisms of protection provided by...

    E. R. Job, T. Ysenbaert, A. Smet, A. Van Hecke, L. Meuris, H. Kleanthous, X. Saelens, T. U. Vogel
  • Open Access
    Attenuation of Live-Attenuated Yellow Fever 17D Vaccine Virus Is Localized to a High-Fidelity Replication Complex
    Research Article | Therapeutics and Prevention
    Attenuation of Live-Attenuated Yellow Fever 17D Vaccine Virus Is Localized to a High-Fidelity Replication Complex

    Live-attenuated viral vaccines are highly safe and efficacious but represent complex and often multigenic attenuation mechanisms. Most of these vaccines have been generated empirically by serial passaging of a wild-type (WT) virus in cell culture. One of the safest and most effective live-attenuated vaccines is yellow fever (YF) virus strain 17D, which has been used for over 80 years to control YF disease. The availability of the WT...

    Emily H. Davis, Andrew S. Beck, Ashley E. Strother, Jill K. Thompson, Steven G. Widen, Stephen Higgs, Thomas G. Wood, Alan D. T. Barrett
  • Open Access
    Human <em>V<sub>H</sub>1-69</em> Gene-Encoded Human Monoclonal Antibodies against <span class="named-content genus-species" id="named-content-1">Staphylococcus aureus</span> IsdB Use at Least Three Distinct Modes of Binding To Inhibit Bacterial Growth and Pathogenesis
    Research Article | Therapeutics and Prevention
    Human VH1-69 Gene-Encoded Human Monoclonal Antibodies against Staphylococcus aureus IsdB Use at Least Three Distinct Modes of Binding To Inhibit Bacterial Growth and Pathogenesis

    The human pathogen Staphylococcus aureus causes a wide range of infections, including skin abscesses and sepsis. There is currently no licensed vaccine to prevent S. aureus infection, and its treatment has become increasingly difficult due to antibiotic resistance. One potential way to inhibit...

    Monique R. Bennett, Jinhui Dong, Robin G. Bombardi, Cinque Soto, Helen M. Parrington, Rachel S. Nargi, Clara T. Schoeder, Marcus B. Nagel, Kevin L. Schey, Jens Meiler, Eric P. Skaar, James E. Crowe

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