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dc.contributor.authorFernández Álvaro, Elena
dc.contributor.authorVoong Vinh, Phat
dc.contributor.authorde Cozar, Cristina
dc.contributor.authorWillé, David R
dc.contributor.authorUrones, Beatriz
dc.contributor.authorCortés, Alvaro
dc.contributor.authorPrice, Alan
dc.contributor.authorTran Do Hoang, Nhu
dc.contributor.authorHa Thanh, Tuyen
dc.contributor.authorMcCloskey, Molly
dc.contributor.authorShaheen, Shareef
dc.contributor.authorDayao, Denise
dc.contributor.authorMartinot, Amanda
dc.contributor.authorde Mercado, Jaime
dc.contributor.authorCastañeda, Pablo
dc.contributor.authorGarcía-Perez, Adolfo
dc.contributor.authorSinga, Benson
dc.contributor.authorPavlinac, Patricia
dc.contributor.authorWalson, Judd
dc.contributor.authorMartínez-Martínez, Maria Santos
dc.contributor.authorArnold, Samuel LM
dc.contributor.authorTzipori, Saul
dc.contributor.authorBallell Pages, Lluis
dc.contributor.authorBaker, Stephen
dc.date.accessioned2022-04-19T13:16:19Z
dc.date.available2022-04-19T13:16:19Z
dc.date.issued2022-03-15
dc.identifier.issn2050-084X
dc.identifier.other35289746
dc.identifier.otherPMC8959600
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/336141
dc.description.abstractBACKGROUND: 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).
dc.languageeng
dc.publishereLife Sciences Publications, Ltd
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceessn: 2050-084X
dc.sourcenlmid: 101579614
dc.subjectMicrobiology
dc.subjectInfectious disease
dc.subjectShigella spp
dc.subjectMulti-drug resistance
dc.subjectDiarrhoea
dc.subjectDysentery
dc.subjectepidemiology
dc.subjectdrug discovery
dc.subjectGlobal Health
dc.subjectCarbapenems
dc.titleThe repurposing of Tebipenem pivoxil as alternative therapy for severe gastrointestinal infections caused by extensively drug-resistant Shigella spp.
dc.typeArticle
dc.date.updated2022-04-19T13:16:18Z
prism.publicationNameElife
prism.volume11
dc.identifier.doi10.17863/CAM.83566
dcterms.dateAccepted2022-03-09
rioxxterms.versionofrecord10.7554/eLife.69798
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidFernández Álvaro, Elena [0000-0001-9287-5012]
dc.contributor.orcidBaker, Stephen [0000-0003-1308-5755]
dc.identifier.eissn2050-084X
pubs.funder-project-idWellcome Trust (215515/Z/19/Z)
cam.issuedOnline2022-03-15


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International