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Nitro-Group-Containing Thiopeptide Derivatives as Promising Agents to Target Clostridioides difficile Kim, Dahyun; Kim, Young-Rok; Hwang, Hee-Jong; Ciufolini, Marco A.; Lee, Jusuk; Lee, Hakyeong; Clovis, Shyaka; Jung, Sungji; Oh, Sang-Hun; Son, Young-Jin; et al.

Abstract

The US Centers for Disease Control and Prevention (CDC) lists Clostridioides difficile as an urgent bacterial threat. Yet, only two drugs, vancomycin and fidaxomicin, are approved by the FDA for the treatment of C. difficile infections as of this writing, while the global pipeline of new drugs is sparse at best. Thus, there is a clear and urgent need for new antibiotics against that organism. Herein, we disclose that AJ-024, a nitroimidazole derivative of a 26-membered thiopeptide, is a promising anti-C. difficile lead compound. Despite their unique mode of action, thiopeptides remain largely unexploited as anti-infective agents. AJ-024 combines potent in vitro activity against various strains of C. difficile with a noteworthy safety profile and desirable pharmacokinetic properties. Its time-kill kinetics against a hypervirulent C. difficile ribotype 027 and in vivo (mouse) efficacy compare favorably to vancomycin, and they define AJ-024 as a valuable platform for the development of new anti-C. difficile antibiotics.

Item Metadata

Title
Nitro-Group-Containing Thiopeptide Derivatives as Promising Agents to Target Clostridioides difficile
Creator
Kim, Dahyun; Kim, Young-Rok; Hwang, Hee-Jong; Ciufolini, Marco A.; Lee, Jusuk; Lee, Hakyeong; Clovis, Shyaka; Jung, Sungji; Oh, Sang-Hun; Son, Young-Jin; Kwak, Jin-Hwan
Publisher
Multidisciplinary Digital Publishing Institute
Date Issued
2022-05-19
Description
The US Centers for Disease Control and Prevention (CDC) lists Clostridioides difficile as an urgent bacterial threat. Yet, only two drugs, vancomycin and fidaxomicin, are approved by the FDA for the treatment of C. difficile infections as of this writing, while the global pipeline of new drugs is sparse at best. Thus, there is a clear and urgent need for new antibiotics against that organism. Herein, we disclose that AJ-024, a nitroimidazole derivative of a 26-membered thiopeptide, is a promising anti-C. difficile lead compound. Despite their unique mode of action, thiopeptides remain largely unexploited as anti-infective agents. AJ-024 combines potent in vitro activity against various strains of C. difficile with a noteworthy safety profile and desirable pharmacokinetic properties. Its time-kill kinetics against a hypervirulent C. difficile ribotype 027 and in vivo (mouse) efficacy compare favorably to vancomycin, and they define AJ-024 as a valuable platform for the development of new anti-C. difficile antibiotics.
Subject
Clostridioides difficile; thiopeptide antibiotics; nitro-group-containing antibiotics
Genre
Article
Type
Text
Language
eng
Date Available
2022-08-26
Provider
Vancouver : University of British Columbia Library
Rights
CC BY 4.0
DOI
10.14288/1.0417575
URI
http://hdl.handle.net/2429/82561
Affiliation
Science, Faculty of; Non UBC; Chemistry, Department of
Citation
Pharmaceuticals 15 (5): 623 (2022)
Publisher DOI
10.3390/ph15050623
Peer Review Status
Reviewed
Scholarly Level
Faculty; Researcher; Other
Rights URI
https://creativecommons.org/licenses/by/4.0/
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CC BY 4.0