The repurposing of Tebipenem pivoxil as alternative therapy for severe gastrointestinal infections caused by extensively drug resistant Shigella spp.

  1. Elena Fernández Alvaro  Is a corresponding author
  2. Phat Voong Vinh
  3. Cristina de Cozar
  4. David Wille
  5. Beatriz Urones
  6. Alvaro Cortés
  7. Alan Price
  8. Nhu Tran Do Hoang
  9. Tuyen Ha Thanh
  10. Molly McCloskey
  11. Shareef Shaheen
  12. Denise Dayao
  13. Jaime de Mercado
  14. Pablo Castañeda
  15. Adolfo García-Perez
  16. Benson Singa
  17. Patricia Pavlinac
  18. Judd Walson
  19. Maria Santos Martínez-Martínez
  20. Samuel LM Arnold
  21. Tzipori Saul
  22. Lluis Ballell
  23. Stephen Baker  Is a corresponding author
  1. GSK Global Health, Spain
  2. Oxford University Clinical Research Unit, Viet Nam
  3. University of Washington School of Medicine, United States
  4. Tufts University, United States
  5. Kenya Medical Research Institute, Kenya
  6. University of Washington, United States
  7. University of Cambridge, United Kingdom

Abstract

Background: Diarrhoea remains one of the leading causes of childhood mortality globally. Recent epidemiological studies conducted in low-middle income countries (LMICs) identified Shigella spp. as the first and second most predominant agent of dysentery and moderate diarrhoea, respectively. Antimicrobial therapy is often necessary for Shigella infections; however, we are reaching a crisis point with efficacious antimicrobials. The rapid emergence of resistance against existing antimicrobials in Shigella spp. poses a serious global health problem.

Methods: Aiming to identify alternative antimicrobial chemicals with activity against antimicrobial resistant Shigella, we initiated a collaborative academia-industry drug discovery project, applying high throughput phenotypic screening across broad chemical diversity and followed a lead compound through in vitro and in vivo characterisation.

Results: We identified several known antimicrobial compound classes with antibacterial activity against Shigella. These compounds included the oral carbapenem Tebipenem, which was found to be highly potent against broadly susceptible Shigella and contemporary MDR variants for which we perform detailed pre-clinical testing. Additional in vitro screening demonstrated that Tebipenem had activity against a wide range of other non-Shigella enteric bacteria. Cognisant of the risk for the development of resistance against monotherapy, we identified synergistic behaviour of two different drug combinations incorporating Tebipenem. We found the orally bioavailable prodrug (Tebipenem pivoxil) had ideal pharmacokinetic properties for treating enteric pathogens and was effective in clearing the gut of infecting organisms when administered to Shigella-infected mice and gnotobiotic piglets.

Conclusions: Our data highlight the emerging antimicrobial resistance crisis and shows that Tebipenem pivoxil (licenced for paediatric respiratory tract infections in Japan) should be accelerated into human trials and could be repurposed as an effective treatment for severe diarrhoea caused by MDR Shigella and other enteric pathogens in LMICs.

Funding: Tres Cantos Open Lab Foundation (projects TC239 and TC246), the Bill and Melinda Gates Foundation (grant OPP1172483) and Wellcome (215515/Z/19/Z).

Data availability

All raw data for this project is available at 10.5281/zenodo.5929105. Exceptions include the propriety compound list owned by GSK. Access to compounds can be requested via the open lab foundation and GSK and the raw MALDI-TOF data are available upon request from the corresponding authors.

The following data sets were generated

Article and author information

Author details

  1. Elena Fernández Alvaro

    GSK Global Health, Madrid, Spain
    For correspondence
    elena.a.fernandez-alvaro@gsk.com
    Competing interests
    Elena Fernández Alvaro, is affiliated with GSK Global Health. The author has no other competing interests to declare..
  2. Phat Voong Vinh

    The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    No competing interests declared.
  3. Cristina de Cozar

    GSK Global Health, Madrid, Spain
    Competing interests
    Cristina de Cozar, is affiliated with GSK Global Health. The author has no other competing interests to declare..
  4. David Wille

    GSK Global Health, Madrid, Spain
    Competing interests
    David Wille, is affiliated with GSK Global Health. The author has no other competing interests to declare..
  5. Beatriz Urones

    GSK Global Health, Madrid, Spain
    Competing interests
    Beatriz Urones, is affiliated with GSK Global Health. The author has no other competing interests to declare..
  6. Alvaro Cortés

    GSK Global Health, Madrid, Spain
    Competing interests
    Alvaro Cortés, is affiliated with GSK Global Health. The author has no other competing interests to declare..
  7. Alan Price

    GSK Global Health, Madrid, Spain
    Competing interests
    Alan Price, is affiliated with GSK Global Health. The author has no other competing interests to declare..
  8. Nhu Tran Do Hoang

    The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    No competing interests declared.
  9. Tuyen Ha Thanh

    The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    No competing interests declared.
  10. Molly McCloskey

    Division of Allergy and Infectious Disease, Center for Emerging and Re-emerging Infectious Diseases, University of Washington School of Medicine, Seattle, United States
    Competing interests
    No competing interests declared.
  11. Shareef Shaheen

    Division of Allergy and Infectious Disease, Center for Emerging and Re-emerging Infectious Diseases, University of Washington School of Medicine, Seattle, United States
    Competing interests
    No competing interests declared.
  12. Denise Dayao

    Department of Infectious Disease and Global Health, Tufts University, North Grafton, United States
    Competing interests
    No competing interests declared.
  13. Jaime de Mercado

    GSK Global Health, Madrid, Spain
    Competing interests
    Jaime de Mercado, is affiliated with GSK Global Health. The author has no other competing interests to declare..
  14. Pablo Castañeda

    GSK Global Health, Madrid, Spain
    Competing interests
    Pablo Castañeda, is affiliated with GSK Global Health. The author has no other competing interests to declare..
  15. Adolfo García-Perez

    GSK Global Health, Madrid, Spain
    Competing interests
    Adolfo García-Perez, is affiliated with GSK Global Health. The author has no other competing interests to declare..
  16. Benson Singa

    Kenya Medical Research Institute, Nairobi, Kenya
    Competing interests
    No competing interests declared.
  17. Patricia Pavlinac

    Department of Global Health, University of Washington, Seattle, United States
    Competing interests
    No competing interests declared.
  18. Judd Walson

    Division of Allergy and Infectious Disease, Center for Emerging and Re-emerging Infectious Diseases, University of Washington School of Medicine, Seattle, United States
    Competing interests
    No competing interests declared.
  19. Maria Santos Martínez-Martínez

    GSK Global Health, Madrid, Spain
    Competing interests
    Maria Santos Martínez-Martínez, is affiliated with GSK Global Health. The author has no other competing interests to declare..
  20. Samuel LM Arnold

    Division of Allergy and Infectious Disease, Center for Emerging and Re-emerging Infectious Diseases, University of Washington School of Medicine, Seattle, United States
    Competing interests
    No competing interests declared.
  21. Tzipori Saul

    Department of Infectious Disease and Global Health, Tufts University, North Grafton, United States
    Competing interests
    No competing interests declared.
  22. Lluis Ballell

    GSK Global Health, Madrid, Spain
    Competing interests
    Lluis Ballell, is affiliated with GSK Global Health. The author has no other competing interests to declare..
  23. Stephen Baker

    Department of Medicine, University of Cambridge, Cambridge, United Kingdom
    For correspondence
    sgb47@medschl.cam.ac.uk
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1308-5755

Funding

GSK Open Lab Foundation (TC239 and TC246)

  • Stephen Baker

Bill and Melinda Gates Foundation (OPP1172483)

  • Lluis Ballell

Wellcome Trust (215515/Z/19/Z)

  • Stephen Baker

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. María Mercedes Zambrano, CorpoGen, Colombia

Ethics

Animal experimentation: All studies were conducted in accordance with the European Directive 2010/63/EEC and the GSK Policy on the Care, Welfare and Treatment of Laboratory Animals or were reviewed by the Institutional Animal Care and Use Committee at the institution where the work was performed.

Version history

  1. Received: April 27, 2021
  2. Accepted: March 9, 2022
  3. Accepted Manuscript published: March 15, 2022 (version 1)
  4. Accepted Manuscript updated: March 21, 2022 (version 2)
  5. Version of Record published: March 28, 2022 (version 3)
  6. Version of Record updated: April 6, 2022 (version 4)
  7. Version of Record updated: September 5, 2022 (version 5)

Copyright

© 2022, Fernández Alvaro et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,809
    views
  • 175
    downloads
  • 5
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Elena Fernández Alvaro
  2. Phat Voong Vinh
  3. Cristina de Cozar
  4. David Wille
  5. Beatriz Urones
  6. Alvaro Cortés
  7. Alan Price
  8. Nhu Tran Do Hoang
  9. Tuyen Ha Thanh
  10. Molly McCloskey
  11. Shareef Shaheen
  12. Denise Dayao
  13. Jaime de Mercado
  14. Pablo Castañeda
  15. Adolfo García-Perez
  16. Benson Singa
  17. Patricia Pavlinac
  18. Judd Walson
  19. Maria Santos Martínez-Martínez
  20. Samuel LM Arnold
  21. Tzipori Saul
  22. Lluis Ballell
  23. Stephen Baker
(2022)
The repurposing of Tebipenem pivoxil as alternative therapy for severe gastrointestinal infections caused by extensively drug resistant Shigella spp.
eLife 11:e69798.
https://doi.org/10.7554/eLife.69798

Share this article

https://doi.org/10.7554/eLife.69798

Further reading

    1. Epidemiology and Global Health
    Yuchen Zhang, Yitang Sun ... Kaixiong Ye
    Research Article

    Background:

    Circulating omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) have been associated with various chronic diseases and mortality, but results are conflicting. Few studies examined the role of omega-6/omega-3 ratio in mortality.

    Methods:

    We investigated plasma omega-3 and omega-6 PUFAs and their ratio in relation to all-cause and cause-specific mortality in a large prospective cohort, the UK Biobank. Of 85,425 participants who had complete information on circulating PUFAs, 6461 died during follow-up, including 2794 from cancer and 1668 from cardiovascular disease (CVD). Associations were estimated by multivariable Cox proportional hazards regression with adjustment for relevant risk factors.

    Results:

    Risk for all three mortality outcomes increased as the ratio of omega-6/omega-3 PUFAs increased (all Ptrend <0.05). Comparing the highest to the lowest quintiles, individuals had 26% (95% CI, 15–38%) higher total mortality, 14% (95% CI, 0–31%) higher cancer mortality, and 31% (95% CI, 10–55%) higher CVD mortality. Moreover, omega-3 and omega-6 PUFAs in plasma were all inversely associated with all-cause, cancer, and CVD mortality, with omega-3 showing stronger effects.

    Conclusions:

    Using a population-based cohort in UK Biobank, our study revealed a strong association between the ratio of circulating omega-6/omega-3 PUFAs and the risk of all-cause, cancer, and CVD mortality.

    Funding:

    Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institute of Health under the award number R35GM143060 (KY). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.