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Article
Stephen Baker
University of Cambridge
Corresponding Author
ORCiD: https://orcid.org/0000-0003-1308-5755
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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. Here, aiming to identify alternative antimicrobial chemicals with activity against multi-drug resistant (MDR) Shigella, we initiated a collaborative academia-industry drug discovery project, applying high throughput phenotypic screening across broad chemical diversity. We identified several suitable compounds 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. 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. The orally bioavailable prodrug (tebipenem pivoxil) effectively cleared the gut of infecting organisms when administered in physiological doses to Shigella-infected mice and gnotobiotic piglets. Our data highlight the utility of broad compound screening for tackling the emerging antimicrobial resistance crisis and shows that tebipenem pivoxil (licenced for paediatric respiratory tract infections in Japan) could be repurposed as an effective treatment for severe diarrhoea caused by MDR Shigella and other enteric pathogens in LMICs.
Keywords
Shigella spp., drug discovery, multi-drug resistance, dysentery, diarrhoea, carbapenems
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This is a list of supplementary files associated with this preprint. Click to download.
- SupplTable1AMRprofileforGSKuploadSep2018.xlsx
Table S1. Antimicrobial susceptibility profile of experimental organisms Attached excel file
- TableS2.pdf
Table S2. Profile and MIC ranges of marketed penem antimicrobials evaluated against S. flexneri EG478 and S. sonnei 02-1181
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This preprint is under consideration at a Nature Portfolio Journal. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Nature journals have partnered with Research Square to offer In Review, a journal-integrated preprint deposition service.
Article
Stephen Baker
University of Cambridge
Corresponding Author
ORCiD: https://orcid.org/0000-0003-1308-5755
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 24 Mar, 2021
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
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. Here, aiming to identify alternative antimicrobial chemicals with activity against multi-drug resistant (MDR) Shigella, we initiated a collaborative academia-industry drug discovery project, applying high throughput phenotypic screening across broad chemical diversity. We identified several suitable compounds 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. 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. The orally bioavailable prodrug (tebipenem pivoxil) effectively cleared the gut of infecting organisms when administered in physiological doses to Shigella-infected mice and gnotobiotic piglets. Our data highlight the utility of broad compound screening for tackling the emerging antimicrobial resistance crisis and shows that tebipenem pivoxil (licenced for paediatric respiratory tract infections in Japan) could be repurposed as an effective treatment for severe diarrhoea caused by MDR Shigella and other enteric pathogens in LMICs.
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