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Therapeutics and Prevention

  • Open Access
    A Solution to Antifolate Resistance in Group B <em>Streptococcus</em>: Untargeted Metabolomics Identifies Human Milk Oligosaccharide-Induced Perturbations That Result in Potentiation of Trimethoprim
    Research Article | Therapeutics and Prevention
    A Solution to Antifolate Resistance in Group B Streptococcus: Untargeted Metabolomics Identifies Human Milk Oligosaccharide-Induced Perturbations That Result in Potentiation of Trimethoprim

    Group B Streptococcus is an important human pathogen that causes serious infections during pregnancy which can lead to chorioamnionitis, funisitis, premature rupture of gestational membranes, preterm birth, neonatal sepsis, and death. GBS is evolving antimicrobial resistance mechanisms, and the work presented in this paper provides evidence that prebiotics such as human milk oligosaccharides can act as adjuvants to restore the...

    Schuyler A. Chambers, Rebecca E. Moore, Kelly M. Craft, Harrison C. Thomas, Rishub Das, Shannon D. Manning, Simona G. Codreanu, Stacy D. Sherrod, David M. Aronoff, John A. McLean, Jennifer A. Gaddy, Steven D. Townsend
  • Open Access
    Translation Inhibition by Rocaglates Activates a Species-Specific Cell Death Program in the Emerging Fungal Pathogen <span class="named-content genus-species" id="named-content-1">Candida auris</span>
    Research Article | Therapeutics and Prevention
    Translation Inhibition by Rocaglates Activates a Species-Specific Cell Death Program in the Emerging Fungal Pathogen Candida auris

    Emergence of the fungal pathogen Candida auris has ignited intrigue and alarm within the medical community and the public at large. This pathogen is unusually resistant to antifungals, threatening to overwhelm current management options. By screening a library of structurally diverse molecules, we found that...

    Kali R. Iyer, Luke Whitesell, John A. Porco, Thomas Henkel, Lauren E. Brown, Nicole Robbins, Leah E. Cowen
  • Open Access
    Vaccine-Induced Th1-Type Response Protects against Invasive Group A <em>Streptococcus</em> Infection in the Absence of Opsonizing Antibodies
    Research Article | Therapeutics and Prevention
    Vaccine-Induced Th1-Type Response Protects against Invasive Group A Streptococcus Infection in the Absence of Opsonizing Antibodies

    Availability of a group A Streptococcus vaccine remains an unmet public health need. Here, we tested different adjuvant formulations to improve the protective efficacy of non-M protein vaccine Combo5 in an invasive disease model. We show that novel adjuvants can dramatically shape the type of immune response developed following immunization with Combo5 and significantly improve protection. In addition, protection afforded by...

    Tania Rivera-Hernandez, Mira Syahira Rhyme, Amanda J. Cork, Scott Jones, Celia Segui-Perez, Livia Brunner, Johanna Richter, Nikolai Petrovsky, Maria Lawrenz, David Goldblatt, Nicolas Collin, Mark J. Walker
  • Open Access
    New Host-Directed Therapeutics for the Treatment of <span class="named-content genus-species" id="named-content-1">Clostridioides difficile</span> Infection
    Research Article | Therapeutics and Prevention
    New Host-Directed Therapeutics for the Treatment of Clostridioides difficile Infection

    Clostridioides difficile is a spore-forming anaerobic bacterium and the leading cause of antibiotic-associated colitis. With few therapeutic options and high rates of disease recurrence, the need to develop new treatment options is urgent. Prior studies utilizing a repurposing approach identified three nonantibiotic Food and Drug Administration-approved drugs,...

    Jourdan A. Andersson, Alex G. Peniche, Cristi L. Galindo, Prapaporn Boonma, Jian Sha, Ruth Ann Luna, Tor C. Savidge, Ashok K. Chopra, Sara M. Dann
  • Open Access
    <em>In Vivo</em> Targeting of <span class="named-content genus-species" id="named-content-1">Clostridioides difficile</span> Using Phage-Delivered CRISPR-Cas3 Antimicrobials
    Research Article | Therapeutics and Prevention
    In Vivo Targeting of Clostridioides difficile Using Phage-Delivered CRISPR-Cas3 Antimicrobials

    Clostridioides difficile is a bacterial pathogen responsible for significant morbidity and mortality across the globe. Current therapies based on broad-spectrum antibiotics have some clinical success, but approximately 30% of patients have relapses, presumably due to the continued perturbation to the gut microbiota. Here, we show that phages can be engineered with...

    Kurt Selle, Joshua R. Fletcher, Hannah Tuson, Daniel S. Schmitt, Lana McMillan, Gowrinarayani S. Vridhambal, Alissa J. Rivera, Stephanie A. Montgomery, Louis-Charles Fortier, Rodolphe Barrangou, Casey M. Theriot, David G. Ousterout
  • Open Access
    Modulation of Monocyte-Driven Myositis in Alphavirus Infection Reveals a Role for CX<sub>3</sub>CR1<sup>+</sup> Macrophages in Tissue Repair
    Research Article | Therapeutics and Prevention
    Modulation of Monocyte-Driven Myositis in Alphavirus Infection Reveals a Role for CX3CR1+ Macrophages in Tissue Repair

    Arthritogenic alphaviruses cause debilitating inflammatory disease, and current therapies are restricted to palliative approaches. Here, we show that following monocyte-driven muscle inflammation, tissue recovery is associated with the accumulation of CX3CR1+ macrophages in the muscle. Modulating inflammatory monocyte infiltration using immune-modifying microparticles (IMP) reduced tissue damage and inflammation...

    Ali Zaid, Kothila Tharmarajah, Helen Mostafavi, Joseph R. Freitas, Kuo-Ching Sheng, Suan-Sin Foo, Weiqiang Chen, Jelena Vider, Xiang Liu, Nicholas P. West, Lara J. Herrero, Adam Taylor, Laura K. Mackay, Daniel R. Getts, Nicholas J. C. King, Suresh Mahalingam
  • Open Access
    Heterosubtypic Protection Induced by a Live Attenuated Influenza Virus Vaccine Expressing Galactose-α-1,3-Galactose Epitopes in Infected Cells
    Research Article | Therapeutics and Prevention
    Heterosubtypic Protection Induced by a Live Attenuated Influenza Virus Vaccine Expressing Galactose-α-1,3-Galactose Epitopes in Infected Cells

    Influenza A viruses have multiple HA subtypes that are antigenically diverse. Classical influenza virus vaccines are subtype specific, and they cannot induce satisfactory heterosubtypic immunity against multiple influenza virus subtypes. Here, we developed a live attenuated H1N1 influenza virus vaccine that allows the expression of α-Gal epitopes by infected cells. Anti-α-Gal antibody is naturally produced by humans. In the presence of...

    Li-Meng Yan, Sylvia P. N. Lau, Chek Meng Poh, Vera S. F. Chan, Michael C. W. Chan, Malik Peiris, Leo L. M. Poon
  • Open Access
    Repurposed Drugs That Block the Gonococcus-Complement Receptor 3 Interaction Can Prevent and Cure Gonococcal Infection of Primary Human Cervical Epithelial Cells
    Research Article | Therapeutics and Prevention
    Repurposed Drugs That Block the Gonococcus-Complement Receptor 3 Interaction Can Prevent and Cure Gonococcal Infection of Primary Human Cervical Epithelial Cells

    Novel therapies that avert the problem of Neisseria gonorrhoeae with acquired antibiotic resistance are urgently needed. Gonococcal infection of the human cervix is initiated by an interaction between a galactose modification made to its surface appendages, pili, and the I-domain region of (host) complement receptor 3 (CR3). By targeting this crucial gonococcal–I-...

    Jessica Poole, Christopher J. Day, Thomas Haselhorst, Freda E.-C. Jen, Victor J. Torres, Jennifer L. Edwards, Michael P. Jennings
  • Open Access
    A Lassa Fever Live-Attenuated Vaccine Based on Codon Deoptimization of the Viral Glycoprotein Gene
    Research Article | Therapeutics and Prevention
    A Lassa Fever Live-Attenuated Vaccine Based on Codon Deoptimization of the Viral Glycoprotein Gene

    Lassa virus (LASV) infects several hundred thousand people in Western Africa, resulting in many lethal Lassa fever (LF) cases. Licensed LF vaccines are not available, and anti-LF therapy is limited to off-label use of the nucleoside analog ribavirin with uncertain efficacy. We describe the generation of a novel live-attenuated LASV vaccine candidate. This vaccine candidate is based on mutating wild-type (WT) LASV in a key region of the...

    Yingyun Cai, Chengjin Ye, Benson Cheng, Aitor Nogales, Masaharu Iwasaki, Shuiqing Yu, Kurt Cooper, David X. Liu, Randy Hart, Ricky Adams, Tyler Brady, Elena N. Postnikova, Jonathan Kurtz, Marisa St Claire, Jens H. Kuhn, Juan Carlos de la Torre, Luis Martínez-Sobrido
  • Open Access
    HIV Drugs Inhibit Transfer of Plasmids Carrying Extended-Spectrum β-Lactamase and Carbapenemase Genes
    Research Article | Therapeutics and Prevention
    HIV Drugs Inhibit Transfer of Plasmids Carrying Extended-Spectrum β-Lactamase and Carbapenemase Genes

    More and more bacterial infections are becoming resistant to antibiotics. This has made treatment of many infections very difficult. One of the reasons this is such a large problem is that bacteria are able to share their genetic material with other bacteria, and these shared genes often include resistance to a variety of antibiotics, including some of our drugs of last resort. We are addressing this problem by using a fluorescence-...

    Michelle M. C. Buckner, M. Laura Ciusa, Richard W. Meek, Alice R. Moorey, Gregory E. McCallum, Emma L. Prentice, Jeremy P. Reid, Luke J. Alderwick, Alessandro Di Maio, Laura J. V. Piddock

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