The C7-aminomethylpyrrolidine group rescues the activity of a thio-fluoroquinolone

Sarah R.C. Lentz; Pratik R. Chheda; Lisa M. Oppegard; Tyrell R. Towle; Robert J. Kerns; Hiroshi Hiasa

doi:10.1016/j.biochi.2019.02.002

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The C7-aminomethylpyrrolidine group rescues the activity of a thio-fluoroquinolone

Journal article

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The C7-aminomethylpyrrolidine group rescues the activity of a thio-fluoroquinolone

Sarah R.C. Lentz, Pratik R. Chheda, Lisa M. Oppegard, Tyrell R. Towle, Robert J. Kerns and Hiroshi Hiasa

Biochimie, Vol.160, pp.24-27

05/2019

DOI: 10.1016/j.biochi.2019.02.002

PMCID: PMC6462232

PMID: 30763638

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Abstract

A Mg2+-water bridge between the C-3, C-4 diketo moiety of fluoroquinolones and the conserved amino acid residues in the GyrA/ParC subunit is critical for the binding of a fluoroquinolone to a topoisomerase-DNA covalent complex. The fluoroquinolone UING-5-249 (249) can bind to the GyrB subunit through its C7-aminomethylpyrrolidine group. This interaction is responsible for enhanced activities of 249 against the wild type and quinolone-resistant mutant topoisomerases. To further evaluate the effects of the 249-GyrB interaction on fluoroquinolone activity, we examined the activities of decarboxy- and thio-249 against DNA gyrase and conducted docking studies using the structure of a gyrase-ciprofloxacin-DNA ternary complex. We found that the 249-GyrB interaction rescued the activity of thio-249 but not that of decarboxy-249. A C7-group that binds more strongly to the GyrB subunit may allow for modifications at the C-4 position, leading to a novel compound that is active against the wild type and quinolone-resistant pathogens. •Binding of fluoroquinolone 249 to the GyrB subunit enhanced its activity.•Decarboxylation abolished the activity of both 249 and ciprofloxacin.•The 249-GyrB interaction lessened the effect of a modification at the C-4 position.•A C7-group that binds to the GyrB subunit creates compounds with higher potency.

DNA gyrase

Drug design

Fluoroquinolone

Quinolone resistance

Topoisomerase

Details

Title: Subtitle: The C7-aminomethylpyrrolidine group rescues the activity of a thio-fluoroquinolone
Creators: Sarah R.C. Lentz - University of Minnesota
Pratik R. Chheda - University of Iowa
Lisa M. Oppegard - University of Minnesota
Tyrell R. Towle - University of Iowa
Robert J. Kerns - University of Iowa
Hiroshi Hiasa - University of Minnesota
Resource Type: Journal article
Publication Details: Biochimie, Vol.160, pp.24-27
DOI: 10.1016/j.biochi.2019.02.002
PMID: 30763638
PMCID: PMC6462232
NLM abbreviation: Biochimie
ISSN: 0300-9084
eISSN: 1638-6183
Publisher: Elsevier B.V
Grant note: DOI: 10.13039/100000002, name: National Institutes of Health (NIH), award: R01 AI087671; DOI: 10.13039/100000002, name: NIH Predoctoral Training Program in Biotechnology, award: GM008365; DOI: 10.13039/100012675, name: University of Iowa Center for Biocatalysis and Bioprocessing; DOI: 10.13039/100000002, name: NIH Predoctoral Training Program in Pharmacological Sciences, award: GM067795; DOI: 10.13039/100005496, name: American Foundation for Pharmaceutical Education
Language: English
Date published: 05/2019
Academic Unit: Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
Record Identifier: 9984365889202771

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