ATP-competitive DNA gyrase and topoisomerase IV inhibitors as antibacterial agents

ABSTRACT

Introduction: The bacterial topoisomerases DNA gyrase and topoisomerase IV are validated targets for development of novel antibacterial agents. Fluoroquinolones inhibit the catalytic GyrA and/or ParC(GrlA) subunit and have been commonly used, although these have toxicity liabilities that restrict their use. The ATPase GyrB and ParE(GrlB) subunits have been much less explored and after withdrawal of novobiocin, there are no further marketed inhibitors . ATP-competitive inhibitors of GyrB and/or ParE(GrlB) are of special interest, as this target has been validated, and it is expected that many of the problems associated with fluoroquinolones can be avoided.

Areas covered: This review summarises the development of ATP-competitive inhibitors of GyrB and/or ParE(GrlB) as novel antibacterial agents over the last 10 years. Structural features of the new inhibitors and their optimisation strategies are highlighted.

Expert opinion: The development of novel ATP-competitive inhibitors of GyrB and/or ParE(GrlB) is ongoing in industrial and academical research. Development of resistance is one of the most problematic issues, but GyrB/ParE(GrlB) inhibitors do not show cross-resistance with fluoroquinolones. Other common issues, such as low solubility, high protein binding, development of off-target resistance, are related to the structures of the inhibitors themselves, which is thus a main focus of design strategies. With some now in early clinical development, there is reasonable expectation that novel ATP-competitive inhibitors of GyrB/ParE(GrlB) will reach the market in the near future.

KEYWORDS:

• Antibacterial compounds
• topoisomerase IV
• DNA gyrase B
• ATP-competitive inhibitors

Article highlights

• GyrB and ParE(GrlB) are validated antibacterial targets that hold promise as effective antibacterial agents in the coming years

• Dual GyrB/ParE(GrlB) inhibitors are antibacterial agents that show low frequency of resistance

• The ATP-binding pockets of GyrB and ParE(GrlB) are well defined, resulting in inhibitors that cover a similar chemical space

• Optimising excellent leads to provide clinical candidates is a challenging task

• Several companies are working on clinical candidates, and one compound is currently in phase I clinical trials.

This box summarizes key pointscontained in the article.

Acknowledgments

The authors thank Christopher Berrie for proofreading the manuscript

Declaration of interest

All the authors are listed as inventors on a patent (priority date, 3 September 2018) for novel antibacterial agents that acts through inhibition of GyrB/ParE, which is not described in this article. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was funded by the Slovene research agency- Grant P1–0208.