Novel Fluorobenzothiazole as a Dual Inhibitor of Gyrase B and Topoisomerase IV Against Gram-Positive Pathogens

Abstract

Aim: The development of a novel inhibitor targeting gyrase B and topoisomerase IV offers an opportunity to combat multidrug resistance. Methods: We investigated the activity of RBx 10080758 against Gram-positive bacteria in vitro and in vivo. Results: RBx 10080758 showed a potent 50% inhibitory concentration of 0.13 μM and 0.25 μM against gyrase B and topoisomerase IV, respectively, and exhibited strong whole-cell in vitro activity with MIC ranges of 0.015–0.06 and 0.015–0.03 μg/ml against Staphylococcus aureus and Streptococcus pneumoniae, respectively. In a rat thigh infection model with methicillin-resistant S. aureus, RBx 10080758 at 45 mg/kg exhibited a >3 log₁₀ CFU reduction in thigh muscles. Conclusion: RBx 10080758 displayed potent activity against multiple multidrug-resistant Gram-positive bacteria with a dual-targeting mechanism of action.

Tweetable abstract

A novel fluorobenzothiazole, dual inhibitor of gyrase B and topoisomerase IV, showed potent in vitro and in vivo activity against Gram-positive bacteria causing respiratory and skin and soft tissue infections in humans.

Keywords::

• dual inhibitors
• fluorobenzothiazole
• Gram-positive bacteria
• gyrase B
• rat thigh infection
• topoisomerase IV

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/fmb-2022-0207

Author contributions

Conceptualization: TKB, MK, VSR, DJU, JS, PKB. Study designed and performed the experiment: TKB, MK, SS, TM, VK, RG, MR, MP, PB, RS, DJU (biology); TC (DMPK and PK); SV, AY, LS, VR, NK, JS (chemistry), supervision: DJU, JS, PKB. All authors contributed to data acquisition, analysis, interpretation and writing the manuscript as well as approved the final version.

Acknowledgments

The authors are thankful to Ranbaxy and Daiichi Sankyo India Pharma Private Limited for providing the necessary facilities to carry out the studies.

Financial & competing interests disclosure

This study was financially supported by Ranbaxy and Daiichi Sankyo India Pharma Private Limited, Gurgaon, India. 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 apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

All animal experiments were approved by the Institutional Animal ethics Committee of Ranbaxy and Daiichi Sankyo India Pharma Private Limited. All animal protocols (IAEC/2010/38, IAEC/2010/42, DS/IAEC-2012/006 and IAEC/2010/77/08-E2/10) were approved by the Institutional Animal Ethics Committee for this project.

Additional information

Funding

This study was financially supported by Ranbaxy and Daiichi Sankyo India Pharma Private Limited, Gurgaon, India. 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 apart from those disclosed.