Actions of a Novel Bacterial Topoisomerase Inhibitor against <i>Neisseria gonorrhoeae</i> Gyrase and Topoisomerase IV: Enhancement of Double-Stranded DNA Breaks
Novel bacterial topoisomerase inhibitors (NBTIs) are an emerging class of antibacterials that target gyrase and topoisomerase IV. A hallmark of NBTIs is their ability to induce gyrase/topoisomerase IV-mediated single-stranded DNA breaks and suppress the generation of double-stranded breaks. However,...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-07-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/15/12107 |
| _version_ | 1797586670612119552 |
|---|---|
| author | Soziema E. Dauda Jessica A. Collins Jo Ann W. Byl Yanran Lu Jack C. Yalowich Mark J. Mitton-Fry Neil Osheroff |
| author_facet | Soziema E. Dauda Jessica A. Collins Jo Ann W. Byl Yanran Lu Jack C. Yalowich Mark J. Mitton-Fry Neil Osheroff |
| author_sort | Soziema E. Dauda |
| collection | DOAJ |
| description | Novel bacterial topoisomerase inhibitors (NBTIs) are an emerging class of antibacterials that target gyrase and topoisomerase IV. A hallmark of NBTIs is their ability to induce gyrase/topoisomerase IV-mediated single-stranded DNA breaks and suppress the generation of double-stranded breaks. However, a previous study reported that some dioxane-linked amide NBTIs induced double-stranded DNA breaks mediated by <i>Staphylococcus aureus</i> gyrase. To further explore the ability of this NBTI subclass to increase double-stranded DNA breaks, we examined the effects of OSUAB-185 on DNA cleavage mediated by <i>Neisseria gonorrhoeae</i> gyrase and topoisomerase IV. OSUAB-185 induced single-stranded and suppressed double-stranded DNA breaks mediated by <i>N. gonorrhoeae</i> gyrase. However, the compound stabilized both single- and double-stranded DNA breaks mediated by topoisomerase IV. The induction of double-stranded breaks does not appear to correlate with the binding of a second OSUAB-185 molecule and extends to fluoroquinolone-resistant <i>N. gonorrhoeae</i> topoisomerase IV, as well as type II enzymes from other bacteria and humans. The double-stranded DNA cleavage activity of OSUAB-185 and other dioxane-linked NBTIs represents a paradigm shift in a hallmark characteristic of NBTIs and suggests that some members of this subclass may have alternative binding motifs in the cleavage complex. |
| first_indexed | 2024-03-11T00:26:20Z |
| format | Article |
| id | doaj.art-57dad8cf2974442080082568e056354a |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T00:26:20Z |
| publishDate | 2023-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-57dad8cf2974442080082568e056354a2023-11-18T23:00:30ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-07-0124151210710.3390/ijms241512107Actions of a Novel Bacterial Topoisomerase Inhibitor against <i>Neisseria gonorrhoeae</i> Gyrase and Topoisomerase IV: Enhancement of Double-Stranded DNA BreaksSoziema E. Dauda0Jessica A. Collins1Jo Ann W. Byl2Yanran Lu3Jack C. Yalowich4Mark J. Mitton-Fry5Neil Osheroff6Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USADepartment of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USADepartment of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USADivision of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USADivision of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 42310, USADivision of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USADepartment of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USANovel bacterial topoisomerase inhibitors (NBTIs) are an emerging class of antibacterials that target gyrase and topoisomerase IV. A hallmark of NBTIs is their ability to induce gyrase/topoisomerase IV-mediated single-stranded DNA breaks and suppress the generation of double-stranded breaks. However, a previous study reported that some dioxane-linked amide NBTIs induced double-stranded DNA breaks mediated by <i>Staphylococcus aureus</i> gyrase. To further explore the ability of this NBTI subclass to increase double-stranded DNA breaks, we examined the effects of OSUAB-185 on DNA cleavage mediated by <i>Neisseria gonorrhoeae</i> gyrase and topoisomerase IV. OSUAB-185 induced single-stranded and suppressed double-stranded DNA breaks mediated by <i>N. gonorrhoeae</i> gyrase. However, the compound stabilized both single- and double-stranded DNA breaks mediated by topoisomerase IV. The induction of double-stranded breaks does not appear to correlate with the binding of a second OSUAB-185 molecule and extends to fluoroquinolone-resistant <i>N. gonorrhoeae</i> topoisomerase IV, as well as type II enzymes from other bacteria and humans. The double-stranded DNA cleavage activity of OSUAB-185 and other dioxane-linked NBTIs represents a paradigm shift in a hallmark characteristic of NBTIs and suggests that some members of this subclass may have alternative binding motifs in the cleavage complex.https://www.mdpi.com/1422-0067/24/15/12107novel bacterial topoisomerase inhibitorNBTItype II topoisomerasegyrasetopoisomerase IVDNA cleavage |
| spellingShingle | Soziema E. Dauda Jessica A. Collins Jo Ann W. Byl Yanran Lu Jack C. Yalowich Mark J. Mitton-Fry Neil Osheroff Actions of a Novel Bacterial Topoisomerase Inhibitor against <i>Neisseria gonorrhoeae</i> Gyrase and Topoisomerase IV: Enhancement of Double-Stranded DNA Breaks International Journal of Molecular Sciences novel bacterial topoisomerase inhibitor NBTI type II topoisomerase gyrase topoisomerase IV DNA cleavage |
| title | Actions of a Novel Bacterial Topoisomerase Inhibitor against <i>Neisseria gonorrhoeae</i> Gyrase and Topoisomerase IV: Enhancement of Double-Stranded DNA Breaks |
| title_full | Actions of a Novel Bacterial Topoisomerase Inhibitor against <i>Neisseria gonorrhoeae</i> Gyrase and Topoisomerase IV: Enhancement of Double-Stranded DNA Breaks |
| title_fullStr | Actions of a Novel Bacterial Topoisomerase Inhibitor against <i>Neisseria gonorrhoeae</i> Gyrase and Topoisomerase IV: Enhancement of Double-Stranded DNA Breaks |
| title_full_unstemmed | Actions of a Novel Bacterial Topoisomerase Inhibitor against <i>Neisseria gonorrhoeae</i> Gyrase and Topoisomerase IV: Enhancement of Double-Stranded DNA Breaks |
| title_short | Actions of a Novel Bacterial Topoisomerase Inhibitor against <i>Neisseria gonorrhoeae</i> Gyrase and Topoisomerase IV: Enhancement of Double-Stranded DNA Breaks |
| title_sort | actions of a novel bacterial topoisomerase inhibitor against i neisseria gonorrhoeae i gyrase and topoisomerase iv enhancement of double stranded dna breaks |
| topic | novel bacterial topoisomerase inhibitor NBTI type II topoisomerase gyrase topoisomerase IV DNA cleavage |
| url | https://www.mdpi.com/1422-0067/24/15/12107 |
| work_keys_str_mv | AT soziemaedauda actionsofanovelbacterialtopoisomeraseinhibitoragainstineisseriagonorrhoeaeigyraseandtopoisomeraseivenhancementofdoublestrandeddnabreaks AT jessicaacollins actionsofanovelbacterialtopoisomeraseinhibitoragainstineisseriagonorrhoeaeigyraseandtopoisomeraseivenhancementofdoublestrandeddnabreaks AT joannwbyl actionsofanovelbacterialtopoisomeraseinhibitoragainstineisseriagonorrhoeaeigyraseandtopoisomeraseivenhancementofdoublestrandeddnabreaks AT yanranlu actionsofanovelbacterialtopoisomeraseinhibitoragainstineisseriagonorrhoeaeigyraseandtopoisomeraseivenhancementofdoublestrandeddnabreaks AT jackcyalowich actionsofanovelbacterialtopoisomeraseinhibitoragainstineisseriagonorrhoeaeigyraseandtopoisomeraseivenhancementofdoublestrandeddnabreaks AT markjmittonfry actionsofanovelbacterialtopoisomeraseinhibitoragainstineisseriagonorrhoeaeigyraseandtopoisomeraseivenhancementofdoublestrandeddnabreaks AT neilosheroff actionsofanovelbacterialtopoisomeraseinhibitoragainstineisseriagonorrhoeaeigyraseandtopoisomeraseivenhancementofdoublestrandeddnabreaks |