title: Structure-guided design and development of novel benzimidazole class of compounds targeting DNA gyraseB enzyme of Staphylococcus aureus.
abstract: The gyraseB subunit of Staphylococcus aureus DNA gyrase is a well-established and validated target though less explored for the development of novel antimicrobial agents. Starting from the available structural information in PDB (3TTZ), we identified a novel series of benzimidazole used as inhibitors of DNA gyraseB with low micromolar inhibitory activity by employing structure-based drug design strategy. Subsequently, this chemical class of DNA gyrase inhibitors was extensively investigated biologically through in vitro assays, biofilm inhibition assays, cytotoxicity, and in vivo studies. The binding affinity of the most potent inhibitor 10 was further ascertained biophysically through differential scanning fluorimetry. Further, the most potent analogues did not show any signs of cardiotoxicity in Zebra fish ether-a-go-go-related gene (zERG), a major breakthrough among the previously reported cardiotoxic gyraseB inhibitors.
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, Jawahar Nagar, Ranga Reddy District, Hyderabad 500078, Andhra Pradesh, India.
authors.forename: Renuka
authors.initials: R
authors.lastname: Janupally
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, Jawahar Nagar, Ranga Reddy District, Hyderabad 500078, Andhra Pradesh, India.
authors.forename: Variam Ullas
authors.initials: VU
authors.lastname: Jeankumar
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, Jawahar Nagar, Ranga Reddy District, Hyderabad 500078, Andhra Pradesh, India.
authors.forename: Karyakulam Andrews
authors.initials: KA
authors.lastname: Bobesh
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, Jawahar Nagar, Ranga Reddy District, Hyderabad 500078, Andhra Pradesh, India.
authors.forename: Vijay
authors.initials: V
authors.lastname: Soni
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, Jawahar Nagar, Ranga Reddy District, Hyderabad 500078, Andhra Pradesh, India.
authors.forename: Parthiban Brindha
authors.initials: PB
authors.lastname: Devi
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, Jawahar Nagar, Ranga Reddy District, Hyderabad 500078, Andhra Pradesh, India.
authors.forename: Venkat Koushik
authors.initials: VK
authors.lastname: Pulla
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, Jawahar Nagar, Ranga Reddy District, Hyderabad 500078, Andhra Pradesh, India.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Suryadevara
authors.affiliation: Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India.
authors.forename: Keerthana Sharma
authors.initials: KS
authors.lastname: Chennubhotla
authors.affiliation: Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India; Zephase Therapeutics (An Incubated Company at the Dr. Reddy's Institute of Life Sciences), University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India.
authors.forename: Pushkar
authors.initials: P
authors.lastname: Kulkarni
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, Jawahar Nagar, Ranga Reddy District, Hyderabad 500078, Andhra Pradesh, India.
authors.forename: Perumal
authors.initials: P
authors.lastname: Yogeeswari
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, Jawahar Nagar, Ranga Reddy District, Hyderabad 500078, Andhra Pradesh, India. Electronic address: dsriram@hyderabad.bits-pilani.ac.in.
authors.forename: Dharmarajan
authors.initials: D
authors.lastname: Sriram
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D027081:DNA Gyrase / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D059005:Topoisomerase II Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D015027:Zebrafish
chemical_list: D000900:Anti-Bacterial Agents; D001562:Benzimidazoles; D059005:Topoisomerase II Inhibitors; C031000:benzimidazole; D027081:DNA Gyrase
keywords: Antibacterial activity; Biofilm; Cytotoxicity; DNA gyraseB; hERG inhibition