Novel fluorobenzothiazole as a dual inhibitor of gyrase B and topoisomerase IV against Gram-positive pathogens

Tarani K Barman; Manoj Kumar; Tridib Chaira; Smita Singhal; Tarun Mathur; Vandana Kalia; Ramkumar Gangadharan; Madhvi Rao; Manisha Pandya; Pragya Bhateja; Ruchi Sood; Dilip J Upadhyay; Shibu Varughese; Ajay Yadav; Lalima Sharma; Venkataramanan Ramadass; Naresh Kumar; Jitendra Sattigeri; Pradip K Bhatnagar; V Samuel Raj

doi:10.2217/fmb-2022-0207

Novel fluorobenzothiazole as a dual inhibitor of gyrase B and topoisomerase IV against Gram-positive pathogens

Future Microbiol. 2023 Jul:18:625-638. doi: 10.2217/fmb-2022-0207. Epub 2023 Jun 22.

Authors

Tarani K Barman^{1

2}, Manoj Kumar^{1

2

3}, Tridib Chaira^{4

5

6}, Smita Singhal^{1

2}, Tarun Mathur^{1

2}, Vandana Kalia^{1

2}, Ramkumar Gangadharan^{1

2

6}, Madhvi Rao^{1

2}, Manisha Pandya^{1

2}, Pragya Bhateja^{1

2}, Ruchi Sood^{1

2}, Dilip J Upadhyay^{1

2}, Shibu Varughese^{7

8}, Ajay Yadav^{7

8}, Lalima Sharma^{7

8}, Venkataramanan Ramadass^{7

8}, Naresh Kumar^{7

8}, Jitendra Sattigeri^{7

8}, Pradip K Bhatnagar^{7

8}, V Samuel Raj^{1

2

9}

Affiliations

¹ Department of Infectious Diseases, New Drug Discovery Research, Ranbaxy Research Laboratories, R & D III, Sector-18, Gurgaon, 122 015, India.
² Department of Microbiology, Daiichi Sankyo India Pharma Private Limited, Village Sarhaul, Sector-18, Gurgaon, 122 015, India.
³ Research Department, Sidra Medicine, Doha, 26999, Qatar.
⁴ Department of Metabolism & Pharmacokinetics, New Drug Discovery Research, Ranbaxy Research Laboratories, R & D III, Sector-18, Gurgaon, 122 015, India.
⁵ Department of Drug Metabolism & Pharmacokinetics, Daiichi Sankyo India Pharma Private Limited, Village Sarhaul, Sector-18, Gurgaon, 122 015, India.
⁶ Department of Pharmacology, SGT University, Gurugram, 122505, Haryana, India.
⁷ Department of Chemistry, New Drug Discovery Research, Ranbaxy Research Laboratories, R & D III, Sector-18, Gurgaon, 122 015, India.
⁸ Department of Chemistry, Daiichi Sankyo India Pharma Private Limited, Village Sarhaul, Sector-18, Gurgaon, 122 015, India.
⁹ Centre for Drug Design Discovery & Development (C4D), SRM University, Delhi-NCR, Sonepat, 131 029, Haryana, India.

PMID: 37347211
DOI: 10.2217/fmb-2022-0207

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.

Keywords: Gram-positive bacteria; dual inhibitors; fluorobenzothiazole; gyrase B; rat thigh infection; topoisomerase IV.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Bacterial Agents / pharmacology
DNA Topoisomerase IV*
Methicillin-Resistant Staphylococcus aureus*
Microbial Sensitivity Tests
Rats
Topoisomerase II Inhibitors / pharmacology

Substances

DNA Topoisomerase IV
Anti-Bacterial Agents
Topoisomerase II Inhibitors