The repurposing of Tebipenem pivoxil as alternative therapy for severe gastrointestinal infections caused by extensively drug resistant Shigella spp.
- GSK Global Health, Spain
- Oxford University Clinical Research Unit, Viet Nam
- GSK R&D, United Kingdom
- University of Washington School of Medicine, United States
- Tufts University, United States
- Kenya Medical Research Institute, Kenya
- University of Washington, United States
- University of Cambridge, United Kingdom
Abstract
<strong>Background:</strong> 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. <strong>Methods:</strong> 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. <strong>Results:</strong> 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. <strong>Conclusions:</strong> 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. <strong>Funding:</strong> 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.
Article and author information
Author details
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.
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.
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
-
- 2,047
- views
-
- 192
- downloads
-
- 7
- 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)
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
Further reading
-
- Epidemiology and Global Health
- Microbiology and Infectious Disease
Several areas of the world suffer a notably high incidence of Shiga toxin-producing Escherichia coli. To assess the impact of persistent cross-species transmission systems on the epidemiology of E. coli O157:H7 in Alberta, Canada, we sequenced and assembled E. coli O157:H7 isolates originating from collocated cattle and human populations, 2007–2015. We constructed a timed phylogeny using BEAST2 using a structured coalescent model. We then extended the tree with human isolates through 2019 to assess the long-term disease impact of locally persistent lineages. During 2007–2015, we estimated that 88.5% of human lineages arose from cattle lineages. We identified 11 persistent lineages local to Alberta, which were associated with 38.0% (95% CI 29.3%, 47.3%) of human isolates. During the later period, six locally persistent lineages continued to be associated with human illness, including 74.7% (95% CI 68.3%, 80.3%) of reported cases in 2018 and 2019. Our study identified multiple locally evolving lineages transmitted between cattle and humans persistently associated with E. coli O157:H7 illnesses for up to 13 y. Locally persistent lineages may be a principal cause of the high incidence of E. coli O157:H7 in locations such as Alberta and provide opportunities for focused control efforts.
