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Eur J Med Chem. 2018 Jan 1;143:755-768. doi: 10.1016/j.ejmech.2017.11.079. Epub 2017 Dec 2.

Purine analogs targeting the guanine riboswitch as potential antibiotics against Clostridioides difficile.

Author information

1
Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, 3001, 12e av nord, Sherbrooke, Québec, J1H 5N4, Canada; Department of Pharmacology-Physiology, Université de Sherbrooke, 3001, 12e av nord, Sherbrooke, Québec, J1H 5N4, Canada.
2
Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, 3001, 12e av nord, Sherbrooke, Québec, J1H 5N4, Canada; Department of Biology, Université de Sherbrooke, 3001, 12e av nord, Sherbrooke, Québec, J1H 5N4, Canada.
3
Department of Microbiology and Infectious Diseases, Université de Sherbrooke, 3001, 12e av nord, Sherbrooke, Québec, J1H 5N4, Canada.
4
Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, 3001, 12e av nord, Sherbrooke, Québec, J1H 5N4, Canada; Department of Biochemistry, Université de Sherbrooke, 3001, 12e av nord, Sherbrooke, Québec, J1H 5N4, Canada.
5
Department of Microbiology and Infectious Diseases, Université de Sherbrooke, 3001, 12e av nord, Sherbrooke, Québec, J1H 5N4, Canada. Electronic address: louis-charles.fortier@usherbrooke.ca.
6
Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, 3001, 12e av nord, Sherbrooke, Québec, J1H 5N4, Canada; Department of Biology, Université de Sherbrooke, 3001, 12e av nord, Sherbrooke, Québec, J1H 5N4, Canada. Electronic address: daniel.lafontaine@usherbrooke.ca.
7
Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, 3001, 12e av nord, Sherbrooke, Québec, J1H 5N4, Canada; Department of Pharmacology-Physiology, Université de Sherbrooke, 3001, 12e av nord, Sherbrooke, Québec, J1H 5N4, Canada. Electronic address: eric.marsault@usherbrooke.ca.

Abstract

Riboswitches recently emerged as possible targets for the development of alternative antimicrobial approaches. Guanine-sensing riboswitches in the bacterial pathogen Clostridioides difficile (formerly known as Clostridium difficile) constitute potential targets based on their involvement in the regulation of basal metabolic control of purine compounds. In this study, we deciphered the structure-activity relationship of several guanine derivatives on the guanine riboswitch and determined their antimicrobial activity. We describe the synthesis of purine analogs modified in ring B as well as positions 2 and 6. Their biological activity was determined by measuring their affinity for the C. difficile guanine riboswitch and their inhibitory effect on bacterial growth, including a counter-screen to discriminate against riboswitch-independent antibacterial effects. Altogether, our results suggest that improvements in riboswitch binding affinity in vitro do not necessarily translate into improved antibacterial activity in bacteria, despite the fact that some structure-activity relationship was observed at least with respect to binding affinity.

KEYWORDS:

Antibiotics; Clostridioides difficile; Clostridium difficile; Guanine; Riboswitch

PMID:
29220796
DOI:
10.1016/j.ejmech.2017.11.079
[Indexed for MEDLINE]

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