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Topoisomerase Inhibitors: Future Perspectives and Challenges
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Topoisomerase Inhibitors: Future Perspectives and Challenges

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: 30 July 2025 | Viewed by 4421

Special Issue Editors

Dr. Ben Bax

E-Mail Website
Guest Editor
Medicines Discovery Institute, Cardiff University, Cardiff, UK
Interests: DNA topoisomerase inhibitors; structural biology; racemase
Dr. Mark Mitton-Fry

E-Mail Website
Guest Editor
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA
Interests: bacterial topoisomerase inhibitors; medicinal chemistry; drug discovery

Special Issue Information

Dear Colleagues,

The means by which topoisomerases regulate DNA (and RNA) topology by cleaving one or both strands of a duplex are questions which small molecules can help to answer. New anticancer and antibacterial compounds that stabilize DNA-cleavage complexes or compete for the ATP binding site of human or bacterial topoisomerases have been identified and are being developed. The anticipated approval of the NBTI gepotidacin to treat uncomplicated urinary tract infections (UTIs) and the successful completion of the SPT zoliflodacin Phase 3 trial to treat gonorrhea will expand the chemotype and resistance profiles of antibacterial topoisomerase drugs. Several new quinolones with improved attributes have been approved as new antibacterials in the 21st century, despite liabilities (including resistance). The benefits for patients of new topoisomerase inhibitors depend on improving both target and mitigating non-target activities. Hence, this Special Issue will attempt to answer the question of what new chemotypes and classes of topoisomerase inhibitors will emerge as drugs in the 21st century.

This Special Issue focuses on topoisomerase inhibitors and welcomes both original research articles and review papers to advance our understanding of topoisomerase inhibitors and their development primarily, though not exclusively, for the benefit of human health. 

Dr. Ben Bax
Dr. Mark Mitton-Fry
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • antibiotic
  • topoisomerase
  • inhibitor
  • anticancer
  • resistance
  • safety

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Published Papers (3 papers)

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Research

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20 pages, 3003 KiB  
Article
Dual Topoisomerase Inhibitor Is Highly Potent and Improves Antitumor Response to Radiotherapy in Cervical Carcinoma
by Inken Flörkemeier, Hannah L. Hotze, Anna Lena Heyne, Jonas Hildebrandt, Jörg P. Weimer, Nina Hedemann, Christoph Rogmans, David Holthaus, Frank-André Siebert, Markus Hirt, Robert Polten, Michael Morgan, Rüdiger Klapdor, Axel Schambach, Astrid Dempfle, Nicolai Maass, Marion T. van Mackelenbergh, Bernd Clement and Dirk O. Bauerschlag
Int. J. Mol. Sci. 2025, 26(7), 2829; https://doi.org/10.3390/ijms26072829 - 21 Mar 2025
Viewed by 421
Abstract
Despite advances in vaccination and early detection, the total number of cases and deaths from cervical cancer has risen steadily in recent decades, making it the fourth most common type of cancer in women worldwide. Low-income countries in particular struggle with limited resources [...] Read more.
Despite advances in vaccination and early detection, the total number of cases and deaths from cervical cancer has risen steadily in recent decades, making it the fourth most common type of cancer in women worldwide. Low-income countries in particular struggle with limited resources and treatment limitations for cervical cancer. Thus, effective medicines that are simple to manufacture are needed. The newly developed dual topoisomerase inhibitor P8-D6, with its outstanding ability to induce apoptosis, could be a promising option. In this study, the efficacy of P8-D6 in combination with radiochemotherapy against cervical carcinoma was investigated in established cell lines and in a translational approach in ex vivo patient cells by measuring the cytotoxicity, cell viability and caspase activity in vitro in 2D and 3D cell cultures. Treatment with P8-D6 resulted in significantly greater cytotoxicity and apoptosis induction compared to standard therapeutic cisplatin in both 2D and 3D cell cultures. Specifically, a considerably stronger anti-proliferative effect was observed. The treatment also led to morphological changes and a loss of membrane integrity in the 3D spheroids. Radiotherapy also benefited greatly from P8-D6 treatment. In fact, P8-D6 was a more potent radiosensitizer than cisplatin. Simple synthesis, favorable physicochemical properties and high potency make P8-D6 a promising cervical cancer drug candidate. Full article
(This article belongs to the Special Issue Topoisomerase Inhibitors: Future Perspectives and Challenges)
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20 pages, 6222 KiB  
Article
How Do Gepotidacin and Zoliflodacin Stabilize DNA Cleavage Complexes with Bacterial Type IIA Topoisomerases? 1. Experimental Definition of Metal Binding Sites
by Harry Morgan, Robert A. Nicholls, Anna J. Warren, Simon E. Ward, Gwyndaf Evans, Fei Long, Garib N. Murshudov, Ramona Duman and Benjamin D. Bax
Int. J. Mol. Sci. 2024, 25(21), 11688; https://doi.org/10.3390/ijms252111688 - 30 Oct 2024
Cited by 2 | Viewed by 1367
Abstract
One of the challenges for experimental structural biology in the 21st century is to see chemical reactions happen. Staphylococcus aureus (S. aureus) DNA gyrase is a type IIA topoisomerase that can create temporary double-stranded DNA breaks to regulate DNA topology. Drugs, [...] Read more.
One of the challenges for experimental structural biology in the 21st century is to see chemical reactions happen. Staphylococcus aureus (S. aureus) DNA gyrase is a type IIA topoisomerase that can create temporary double-stranded DNA breaks to regulate DNA topology. Drugs, such as gepotidacin, zoliflodacin and the quinolone moxifloxacin, can stabilize these normally transient DNA strand breaks and kill bacteria. Crystal structures of uncleaved DNA with a gepotidacin precursor (2.1 Å GSK2999423) or with doubly cleaved DNA and zoliflodacin (or with its progenitor QPT-1) have been solved in the same P61 space-group (a = b ≈ 93 Å, c ≈ 412 Å). This suggests that it may be possible to observe the two DNA cleavage steps (and two DNA-religation steps) in this P61 space-group. Here, a 2.58 Å anomalous manganese dataset in this crystal form is solved, and four previous crystal structures (1.98 Å, 2.1 Å, 2.5 Å and 2.65 Å) in this crystal form are re-refined to clarify crystal contacts. The structures clearly suggest a single moving metal mechanism—presented in an accompanying (second) paper. A previously published 2.98 Å structure of a yeast topoisomerase II, which has static disorder around a crystallographic twofold axis, was published as containing two metals at one active site. Re-refined coordinates of this 2.98 Å yeast structure are consistent with other type IIA topoisomerase structures in only having one metal ion at each of the two different active sites. Full article
(This article belongs to the Special Issue Topoisomerase Inhibitors: Future Perspectives and Challenges)
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Review

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17 pages, 1314 KiB  
Review
Etoposide as a Key Therapeutic Agent in Lung Cancer: Mechanisms, Efficacy, and Emerging Strategies
by Jung Yoon Jang, Donghwan Kim, Eunok Im and Nam Deuk Kim
Int. J. Mol. Sci. 2025, 26(2), 796; https://doi.org/10.3390/ijms26020796 - 18 Jan 2025
Cited by 1 | Viewed by 1743
Abstract
Topoisomerase II inhibitors, particularly etoposide, have long been integral to the treatment of lung cancer, especially small cell lung cancer. This review comprehensively examines the mechanisms of action of etoposide, its clinical efficacy, and its role in current lung cancer treatment regimens. Etoposide [...] Read more.
Topoisomerase II inhibitors, particularly etoposide, have long been integral to the treatment of lung cancer, especially small cell lung cancer. This review comprehensively examines the mechanisms of action of etoposide, its clinical efficacy, and its role in current lung cancer treatment regimens. Etoposide exerts its anticancer effects by inducing DNA strand breaks through the inhibition of topoisomerase II, leading to cancer cell apoptosis. Despite their widespread use, challenges such as drug resistance, toxicity, and limited efficacy in non-small cell lung cancer have spurred ongoing research on combination therapies and novel drug formulations. Emerging therapeutic strategies include the integration of etoposide with immunotherapy, targeted therapies, and novel drug delivery systems aimed at enhancing the therapeutic window and overcoming drug resistance. This article aims to inform the development of more effective treatment strategies by providing a critical overview of the clinical applications of etoposide and exploring future directions for lung cancer therapy. Full article
(This article belongs to the Special Issue Topoisomerase Inhibitors: Future Perspectives and Challenges)
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