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

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

Pharmacology

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

A Mg ²⁺ -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.

Original language	English (US)
Pages (from-to)	24-27
Number of pages	4
Journal	Biochimie
Volume	160
DOIs	https://doi.org/10.1016/j.biochi.2019.02.002
State	Published - May 2019

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health (NIH) grant R01 AI087671 (to RJK). PRC acknowledges support of the NIH Predoctoral Training Program in Biotechnology ( GM008365 ) and the University of Iowa Center for Biocatalysis and Bioprocessing fellowship. TRT acknowledges support of the NIH Predoctoral Training Program in Pharmacological Sciences ( GM067795 ), the American Foundation for Pharmaceutical Education Predoctoral Fellowship Program, and the American Chemical Society Division of Medicinal Chemistry Fellowship sponsored by Richard B. Silverman.

Publisher Copyright:
© 2019 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM)

Keywords

DNA gyrase
Drug design
Fluoroquinolone
Quinolone resistance
Topoisomerase

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "The C7-aminomethylpyrrolidine group rescues the activity of a thio-fluoroquinolone",

abstract = " A Mg 2+ -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.",

keywords = "DNA gyrase, Drug design, Fluoroquinolone, Quinolone resistance, Topoisomerase",

author = "Lentz, {Sarah R.C.} and Chheda, {Pratik R.} and Oppegard, {Lisa M.} and Towle, {Tyrell R.} and Kerns, {Robert J.} and Hiroshi Hiasa",

note = "Funding Information: This work was supported by the National Institutes of Health (NIH) grant R01 AI087671 (to RJK). PRC acknowledges support of the NIH Predoctoral Training Program in Biotechnology ( GM008365 ) and the University of Iowa Center for Biocatalysis and Bioprocessing fellowship. TRT acknowledges support of the NIH Predoctoral Training Program in Pharmacological Sciences ( GM067795 ), the American Foundation for Pharmaceutical Education Predoctoral Fellowship Program, and the American Chemical Society Division of Medicinal Chemistry Fellowship sponsored by Richard B. Silverman. Publisher Copyright: {\textcopyright} 2019 Elsevier B.V. and Soci{\'e}t{\'e} Fran{\c c}aise de Biochimie et Biologie Mol{\'e}culaire (SFBBM)",

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T1 - The C7-aminomethylpyrrolidine group rescues the activity of a thio-fluoroquinolone

AU - Lentz, Sarah R.C.

AU - Chheda, Pratik R.

AU - Oppegard, Lisa M.

AU - Towle, Tyrell R.

AU - Kerns, Robert J.

AU - Hiasa, Hiroshi

N1 - Funding Information: This work was supported by the National Institutes of Health (NIH) grant R01 AI087671 (to RJK). PRC acknowledges support of the NIH Predoctoral Training Program in Biotechnology ( GM008365 ) and the University of Iowa Center for Biocatalysis and Bioprocessing fellowship. TRT acknowledges support of the NIH Predoctoral Training Program in Pharmacological Sciences ( GM067795 ), the American Foundation for Pharmaceutical Education Predoctoral Fellowship Program, and the American Chemical Society Division of Medicinal Chemistry Fellowship sponsored by Richard B. Silverman. Publisher Copyright: © 2019 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM)

PY - 2019/5

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N2 - A Mg 2+ -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.

AB - A Mg 2+ -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.

KW - DNA gyrase

KW - Drug design

KW - Fluoroquinolone

KW - Quinolone resistance

KW - Topoisomerase

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JO - Biochimie

JF - Biochimie

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

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