Published May 18, 2021 | Version 2
Dataset Open

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

Creators

  • 1. Univesrity of Cambridge

Description

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

Elena Fernández Alvaro 1*, Phat Voong Vinh 2, Cristina de Cozar 1, David Wille 1, Beatriz Urones 1,

Alan Price 1, Nhu Tran Do Hoang 2, Tuyen Ha Thanh 2, Molly McCloskey 3, Shareef Shaheen 3, Denise Dayao 4, Jaime de Mercado 1, Pablo Castañeda 1, Adolfo García-Perez 1, Benson Singa 5, Patricia Pavlinac 6,

Judd Walson3, Maria Santos Martínez-Martínez 1, Samuel L.M. Arnold 3, Tzipori Saul 4, Lluis Ballell 1#,

and Stephen Baker 7,8*

 

Notes

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).

Files

15_Jeju_pivox.tif

Files (38.2 MB)

Name Size Download all
md5:a6bdcb7d4f866afe38a1d60395729c84
343.8 kB Preview Download
md5:5e83d202883935163d21cacb418b8588
789.5 kB Preview Download
md5:fd8fcbcce27f0eb8b176cc8361d4bfcc
242.4 kB Preview Download
md5:428390ce85f7ab48e7a6afa69109103d
272.7 kB Preview Download
md5:3596744036d71805373354b42f768d1c
176.4 kB Preview Download
md5:8e0a8d1359962c132cba55c1212fd9f7
219.2 kB Preview Download
md5:eeaee17136ca1a680ef660069f7c8353
198.9 kB Preview Download
md5:b5dece94deaec868726fceb300624822
278.0 kB Preview Download
md5:3aabfc1101d5111822219baccf7f1ec3
191.3 kB Preview Download
md5:fcfbe41920558f6c04f04f03ff51eec0
852.5 kB Preview Download
md5:60eaf6a2eb0b52d26ff177dd37cb2385
259.1 kB Preview Download
md5:bc9e645692937d3eeedde771810365fd
315.0 kB Preview Download
md5:d73858548eee87ab4eed64f09eb8621c
148.2 kB Preview Download
md5:f756d4f38bcd4d56c3ffb80f36033619
186.5 kB Preview Download
md5:dd7761968b60cc7d1399ae2660fd8a25
170.3 kB Preview Download
md5:e9db6eaeb7ebd35f5f18ba5966e93fe4
252.0 kB Preview Download
md5:c0f46e39bc2990fca6fd52595e5d8176
129.5 kB Preview Download
md5:7e82d56e3b85a62d55941d59977939b7
148.6 kB Preview Download
md5:68618ab0728b688a7bdc966e36bf9130
114.0 kB Preview Download
md5:660bce161bcf7f50213f3d97ce71a771
158.8 kB Preview Download
md5:6d4efc7b1eb99c520c9545846ac699be
8.4 MB Preview Download
md5:62412cecd755c7558af79bed254105f4
5.9 MB Preview Download
md5:1cb200ef2548dff7845a8b7db6536492
5.3 MB Preview Download
md5:2f952b61c5781dfa230dd9982ea2711e
1.5 MB Preview Download
md5:68f90f72ecdf5b0025584f5eaf902589
1.7 MB Preview Download
md5:59a1d0b4a55ec3d829ad52937f1909da
2.1 MB Preview Download
md5:79431d1cf85d40236c3564520707b8dd
1.2 MB Preview Download
md5:ae134ea1fe110195d8a10cefa3cc3e92
1.7 MB Preview Download
md5:9ce7059bea98cc7dfa405fa04e7bb41d
2.5 MB Preview Download
md5:478b8d0ff5aed2101c804876b3cec8e1
2.4 MB Preview Download
md5:58077dfd9274fdb356db1c390e37477d
26.2 kB Download
md5:a3fa60916f2a0323a1e7faff52d9f197
31.9 kB Download
md5:419130f0efb0c0500a81e986595ce5e6
24.1 kB Download
md5:62cef3cf6458bc2bd10881fc9ec0f9bc
16.0 kB Download
md5:68dca4dbd58ea30e180b1310c86fddc9
141.6 kB Preview Download