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Therapeutics and Prevention

  • Open Access
    Broad and Protective Influenza B Virus Neuraminidase Antibodies in Humans after Vaccination and their Clonal Persistence as Plasma Cells
    Research Article | Therapeutics and Prevention
    Broad and Protective Influenza B Virus Neuraminidase Antibodies in Humans after Vaccination and their Clonal Persistence as Plasma Cells

    Influenza virus infections continue to cause substantial morbidity and mortality despite the availability of seasonal vaccines. The extensive genetic variability in seasonal and potentially pandemic influenza strains necessitates new vaccine strategies that can induce universal protection by focusing the immune response on generating protective antibodies against conserved targets such as regions within the influenza neuraminidase...

    Michael S. Piepenbrink, Aitor Nogales, Madhubanti Basu, Christopher F. Fucile, Jane L. Liesveld, Michael C. Keefer, Alexander F. Rosenberg, Luis Martinez-Sobrido, James J. Kobie
  • Open Access
    Design of Nanoparticulate Group 2 Influenza Virus Hemagglutinin Stem Antigens That Activate Unmutated Ancestor B Cell Receptors of Broadly Neutralizing Antibody Lineages
    Research Article | Therapeutics and Prevention
    Design of Nanoparticulate Group 2 Influenza Virus Hemagglutinin Stem Antigens That Activate Unmutated Ancestor B Cell Receptors of Broadly Neutralizing Antibody Lineages

    Current influenza vaccines are primarily strain specific, requiring annual updates, and offer minimal protection against drifted seasonal or pandemic strains. The highly conserved stem region of hemagglutinin (HA) of group 2 influenza A virus subtypes is a promising target for vaccine elicitation of broad cross-group protection against divergent strains. We used structure-guided protein engineering employing multiple protein...

    Kizzmekia S. Corbett, Syed M. Moin, Hadi M. Yassine, Alberto Cagigi, Masaru Kanekiyo, Seyhan Boyoglu-Barnum, Sky I. Myers, Yaroslav Tsybovsky, Adam K. Wheatley, Chaim A. Schramm, Rebecca A. Gillespie, Wei Shi, Lingshu Wang, Yi Zhang, Sarah F. Andrews, M. Gordon Joyce, Michelle C. Crank, Daniel C. Douek, Adrian B. McDermott, John R. Mascola, Barney S. Graham, Jeffrey C. Boyington
  • Open Access
    Dual β-Lactam Combinations Highly Active against <span class="named-content genus-species" id="named-content-1">Mycobacterium abscessus</span> Complex <em>In Vitro</em>
    Research Article | Therapeutics and Prevention
    Dual β-Lactam Combinations Highly Active against Mycobacterium abscessus Complex In Vitro

    The emergence of chronic MABC infections among immunocompromised populations and their inherent and acquired resistance to effective antibiotic therapy have created clinical challenges in advancing patients for transplant surgery and treating those with disease. There is an urgent need for new treatment regimens, and the repurposing of existing antibiotics provides a rapid strategy to advance a laboratory finding to patient care. Our...

    R. Pandey, L. Chen, C. Manca, S. Jenkins, L. Glaser, C. Vinnard, G. Stone, J. Lee, B. Mathema, E. L. Nuermberger, R. A. Bonomo, B. N. Kreiswirth
  • Open Access
    Didehydro-Cortistatin A Inhibits HIV-1 by Specifically Binding to the Unstructured Basic Region of Tat
    Research Article | Therapeutics and Prevention
    Didehydro-Cortistatin A Inhibits HIV-1 by Specifically Binding to the Unstructured Basic Region of Tat

    Tat activates virus production, and limited Tat transactivation correlates with HIV-1 latency. The Tat inhibitor dCA locks HIV in persistent latency. This drug class enables block-and-lock functional cure approaches, aimed at reducing residual viremia during therapy and limiting viral rebound. dCA may also have additional therapeutic benefits since Tat is also neurotoxic. Unfortunately, Tat inhibitors are not clinically available. We...

    Sonia Mediouni, Krishna Chinthalapudi, Mary K. Ekka, Ippei Usui, Joseph A. Jablonski, Mark A. Clementz, Guillaume Mousseau, Jason Nowak, Venkat R. Macherla, Jacob N. Beverage, Eduardo Esquenazi, Phil Baran, Ian Mitchelle S. de Vera, Douglas Kojetin, Erwann P. Loret, Kendall Nettles, Souvik Maiti, Tina Izard, Susana T. Valente
  • Open Access
    Commensal Bacteria: Not Just Innocent Bystanders
    Commentary | Therapeutics and Prevention
    Commensal Bacteria: Not Just Innocent Bystanders

    Neisseria gonorrhoeae is quickly becoming untreatable due to its acquisition of resistance to multiple antimicrobials. It is vital that we begin to understand the mechanisms by which this is occurring.

    Michael A. Apicella
  • Open Access
    Repurposing Estrogen Receptor Antagonists for the Treatment of Infectious Disease
    Minireview | Therapeutics and Prevention
    Repurposing Estrogen Receptor Antagonists for the Treatment of Infectious Disease

    The concept of repurposing previously approved medications to the treatment of new indications by taking advantage of off-target effects has gained traction in recent years, particularly in areas of medicine that do not offer large profits to pharmaceutical firms. As infectious disease discovery research has declined among large pharmaceutical companies, the potential payoff of repurposing has become attractive.

    Marhiah C. Montoya, Damian J. Krysan
  • Open Access
    Synergistic Lethality of a Binary Inhibitor of <span class="named-content genus-species" id="named-content-1">Mycobacterium tuberculosis</span> KasA
    Research Article | Therapeutics and Prevention
    Synergistic Lethality of a Binary Inhibitor of Mycobacterium tuberculosis KasA

    Cell wall biosynthesis inhibitors have proven highly effective for treating tuberculosis (TB). We discovered and validated members of the indazole sulfonamide class of small molecules as inhibitors of Mycobacterium tuberculosis KasA—a key component for biosynthesis of the mycolic acid layer of the bacterium’s cell wall and the same pathway as that inhibited by the...

    Pradeep Kumar, Glenn C. Capodagli, Divya Awasthi, Riju Shrestha, Karishma Maharaja, Paridhi Sukheja, Shao-Gang Li, Daigo Inoyama, Matthew Zimmerman, Hsin Pin Ho Liang, Jansy Sarathy, Marizel Mina, George Rasic, Riccardo Russo, Alexander L. Perryman, Todd Richmann, Aditi Gupta, Eric Singleton, Sheetal Verma, Seema Husain, Patricia Soteropoulos, Zhe Wang, Roxanne Morris, Gene Porter, Gautam Agnihotri, Padmini Salgame, Sean Ekins, Kyu Y. Rhee, Nancy Connell, Véronique Dartois, Matthew B. Neiditch, Joel S. Freundlich, David Alland
  • Open Access
    Deciphering the Evolution of Cephalosporin Resistance to Ceftolozane-Tazobactam in <span class="named-content genus-species" id="named-content-1">Pseudomonas aeruginosa</span>
    Research Article | Therapeutics and Prevention
    Deciphering the Evolution of Cephalosporin Resistance to Ceftolozane-Tazobactam in Pseudomonas aeruginosa

    The presence of β-lactamases (e.g., PDC-3) that have naturally evolved and acquired the ability to break down β-lactam antibiotics (e.g., ceftazidime and ceftolozane) leads to highly resistant and potentially lethal Pseudomonas aeruginosa infections. We show that wild-type PDC-3 β-lactamase forms an acyl enzyme complex with ceftazidime, but it cannot accommodate the...

    Melissa D. Barnes, Magdalena A. Taracila, Joseph D. Rutter, Christopher R. Bethel, Ioannis Galdadas, Andrea M. Hujer, Emilia Caselli, Fabio Prati, John P. Dekker, Krisztina M. Papp-Wallace, Shozeb Haider, Robert A. Bonomo
  • Open Access
    Antibodies against the Majority Subunit (PilA) of the Type IV Pilus of Nontypeable <span class="named-content genus-species" id="named-content-1">Haemophilus influenzae</span> Disperse <span class="named-content genus-species" id="named-content-2">Moraxella catarrhalis</span> from a Dual-Species Biofilm
    Research Article | Therapeutics and Prevention
    Antibodies against the Majority Subunit (PilA) of the Type IV Pilus of Nontypeable Haemophilus influenzae Disperse Moraxella catarrhalis from a Dual-Species Biofilm

    Middle ear infections (or otitis media [OM]) are highly prevalent among children worldwide and present a tremendous socioeconomic challenge for health care systems. More importantly, this disease diminishes the quality of life of young children. OM is often chronic and recurrent, due to the presence of highly antibiotic-resistant communities of bacteria (called biofilms) that persist within the middle ear space. To combat these...

    Elaine M. Mokrzan, Laura A. Novotny, Kenneth L. Brockman, Lauren O. Bakaletz
  • Open Access
    Chemical Synergy between Ionophore PBT2 and Zinc Reverses Antibiotic Resistance
    Research Article | Therapeutics and Prevention
    Chemical Synergy between Ionophore PBT2 and Zinc Reverses Antibiotic Resistance

    The rise of bacterial antibiotic resistance coupled with a reduction in new antibiotic development has placed significant burdens on global health care. Resistant bacterial pathogens such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus are leading causes of community- and hospital-acquired infection and present a...

    Lisa Bohlmann, David M. P. De Oliveira, Ibrahim M. El-Deeb, Erin B. Brazel, Nichaela Harbison-Price, Cheryl-lynn Y. Ong, Tania Rivera-Hernandez, Scott A. Ferguson, Amanda J. Cork, Minh-Duy Phan, Amelia T. Soderholm, Mark R. Davies, Graeme R. Nimmo, Gordon Dougan, Mark A. Schembri, Gregory M. Cook, Alastair G. McEwan, Mark von Itzstein, Christopher A. McDevitt, Mark J. Walker

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