Bulge oligonucleotide as an inhibitory agent of bacterial topoisomerase I

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Abstract

Bacterial topoisomerase I (Btopo I) was defined as potential target for discovery of new antibacterial compounds. Various oligonucleotides containing bulge structure were designed and synthesised as inhibitors to Btopo I in this investigation. The results of this study demonstrated that the designed oligonucleotides display high inhibitory efficiency on the activity of Btopo I and the inhibitory effect could be modulated by the amount of bulge DNA bases. The most efficient one among them showed an IC ₅₀ value of 63.1 nM in its inhibition on the activity of Btopo I. In addition, our studies confirmed that the designed oligonucleotide would induce irreversible damages to Btopo I and without any effects occur to eukaryotic topoisomerase I. It is our hope that the results provided in these studies could provide a novel way to inhibit Btopo I.

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The Current Case of Quinolones: Synthetic Approaches and Antibacterial Activity

Abdul Naeem, Syed Lal Badshah, Mairman Muska … (2016)

Quinolones are broad-spectrum synthetic antibacterial drugs first obtained during the synthesis of chloroquine. Nalidixic acid, the prototype of quinolones, first became available for clinical consumption in 1962 and was used mainly for urinary tract infections caused by Escherichia coli and other pathogenic Gram-negative bacteria. Recently, significant work has been carried out to synthesize novel quinolone analogues with enhanced activity and potential usage for the treatment of different bacterial diseases. These novel analogues are made by substitution at different sites—the variation at the C-6 and C-8 positions gives more effective drugs. Substitution of a fluorine atom at the C-6 position produces fluroquinolones, which account for a large proportion of the quinolones in clinical use. Among others, substitution of piperazine or methylpiperazine, pyrrolidinyl and piperidinyl rings also yields effective analogues. A total of twenty six analogues are reported in this review. The targets of quinolones are two bacterial enzymes of the class II topoisomerase family, namely gyrase and topoisomerase IV. Quinolones increase the concentration of drug-enzyme-DNA cleavage complexes and convert them into cellular toxins; as a result they are bactericidal. High bioavailability, relative low toxicity and favorable pharmacokinetics have resulted in the clinical success of fluoroquinolones and quinolones. Due to these superior properties, quinolones have been extensively utilized and this increased usage has resulted in some quinolone-resistant bacterial strains. Bacteria become resistant to quinolones by three mechanisms: (1) mutation in the target site (gyrase and/or topoisomerase IV) of quinolones; (2) plasmid-mediated resistance; and (3) chromosome-mediated quinolone resistance. In plasmid-mediated resistance, the efflux of quinolones is increased along with a decrease in the interaction of the drug with gyrase (topoisomerase IV). In the case of chromosome-mediated quinolone resistance, there is a decrease in the influx of the drug into the cell.

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Human DNA topoisomerase I: relaxation, roles, and damage control.

J A Champoux, John B. Leppard (2005)

Human DNA topoisomerase I is an essential enzyme involved in resolving the torsional stress associated with DNA replication, transcription, and chromatin condensation. The catalytic cycle of the enzyme consists of DNA cleavage to form a covalent enzyme-DNA intermediate, DNA relaxation, and finally, re-ligation of the phosphate backbone to restore the continuity of the DNA. Structure/function studies have elucidated a flexible enzyme that relaxes DNA through coordinated, controlled movements of distinct enzyme domains. The cellular roles of topoisomerase I are apparent throughout the nucleus, but the concentration of processes acting on ribosomal DNA results in topoisomerase I accumulation in the nucleolus. Although the activity of topoisomerase I is required in these processes, the enzyme can also have a deleterious effect on cells. In the event that the final re-ligation step of the reaction cycle is prevented, the covalent topoisomerase I-DNA intermediate becomes a toxic DNA lesion that must be repaired. The complexities of the relaxation reaction, the cellular roles, and the pathways that must exist to repair topoisomerase I-mediated DNA damage highlight the importance of continued study of this essential enzyme.

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DNA Topology and Topoisomerases: Teaching a "Knotty" Subject.

Joseph Deweese, Neil Osheroff, Jerome Osheroff (2007)

DNA is essentially an extremely long double-stranded rope in which the two strands are wound about one another. As a result, topological properties of the genetic material, including DNA underwinding and overwinding, knotting, and tangling, profoundly influence virtually every major nucleic acid process. Despite the importance of DNA topology, it is a conceptionally difficult subject to teach, because it requires students to visualize three-dimensional relationships. This article will familiarize the reader with the concept of DNA topology and offer practical approaches and demonstrations to teaching this "knotty" subject in the classroom. Furthermore, it will discuss topoisomerases, the enzymes that regulate the topological state of DNA in the cell. These ubiquitous enzymes perform a number of critical cellular functions by generating transient breaks in the double helix. During this catalytic event, topoisomerases maintain genomic stability by forming covalent phosphotyrosyl bonds between active site residues and the newly generated DNA termini. Topoisomerases are essential for cell survival. However, because they cleave the genetic material, these enzymes also have the potential to fragment the genome. This latter feature of topoisomerases is exploited by some of the most widely prescribed anticancer and antibacterial drugs currently in clinical use. Finally, in addition to curing cancer, topoisomerase action also has been linked to the induction of specific types of leukemia.

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Author and article information

Journal

Journal ID (nlm-ta): J Enzyme Inhib Med Chem

Journal ID (iso-abbrev): J Enzyme Inhib Med Chem

Journal ID (publisher-id): IENZ

Journal ID (publisher-id): ienz20

Title: Journal of Enzyme Inhibition and Medicinal Chemistry

Publisher: Taylor & Francis

ISSN (Print): 1475-6366

ISSN (Electronic): 1475-6374

Publication date Collection: 2018

Publication date (Electronic): 28 December 2017

Volume: 33

Issue: 1

Pages: 319-323

Affiliations

[a ]School of Pharmaceutical Sciences, Jiangnan University , Jiangsu, People’s Republic of China;

[b ]Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, School of Food Science and Technology, Jiangnan University , Jiangsu, People’s Republic of China

Author notes

Supplemental data for this article can be accessed here .

CONTACT Zhaoqi Yang zhaoqiyang@ 123456jiangnan.edu.cn School of Pharmaceutical Sciences, Jiangnan University , Jiangsu214122, People’s Republic of China

Article

Publisher ID: 1419218

DOI: 10.1080/14756366.2017.1419218

PMC ID: 6009931

PubMed ID: 29281935

SO-VID: 21274c8f-30fe-43e0-a5df-350d9172b9b9

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 06 October 2017

Date revision received : 17 November 2017

Date accepted : 12 December 2017

Page count

Pages: 5, Words: 3761

Funding

Funded by: National Natural Science Foundation of China 10.13039/501100001809

Award ID: 81402843

Funded by: Fok Ying-Tong Education Foundation

Award ID: 151028

We are greatly appreciating National Natural Science Foundation of China (No. 81402843), Fok Ying-Tong Education Foundation (No. 151028), and the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry for financial support this research work.

Bulge oligonucleotide as an inhibitory agent of bacterial topoisomerase I

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Most cited references 28

The Current Case of Quinolones: Synthetic Approaches and Antibacterial Activity

Human DNA topoisomerase I: relaxation, roles, and damage control.

DNA Topology and Topoisomerases: Teaching a "Knotty" Subject.

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