title: Bioactivity Studies of β-Lactam Derived Polycyclic Fused Pyrroli-Dine/Pyrrolizidine Derivatives in Dentistry: In Vitro, In Vivo and In Silico Studies.
abstract: The antibacterial activity of β-lactam derived polycyclic fused pyrrolidine/pyrrolizidine derivatives synthesized by 1, 3-dipolar cycloaddition reaction was evaluated against microbes involved in dental infection. Fifteen compounds were screened; among them compound 3 showed efficient antibacterial activity in an ex vivo dentinal tubule model and in vivo mice infectious model. In silico docking studies showed greater affinity to penicillin binding protein. Cell damage was observed under Scanning Electron Microscopy (SEM) which was further proved by Confocal Laser Scanning Microscope (CLSM) and quantified using Flow Cytometry by PI up-take. Compound 3 treated E. faecalis showed ROS generation and loss of membrane integrity was quantified by flow cytometry. Compound 3 was also found to be active against resistant E. faecalis strains isolated from failed root canal treatment cases. Further, compound 3 was found to be hemocompatible, not cytotoxic to normal mammalian NIH 3T3 cells and non mutagenic. It was concluded that β-lactam compound 3 exhibited promising antibacterial activity against E. faecalis involved in root canal infections and the mechanism of action was deciphered. The results of this research can be further implicated in the development of potent antibacterial medicaments with applications in dentistry.
authors.affiliation: Department of Human Genetics, Sri Ramachandra University, Porur, Chennai, Tamilnadu, India.
authors.forename: Gowri
authors.initials: G
authors.lastname: Meiyazhagan
authors.affiliation: Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai, Tamilnadu, India.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Raju
authors.affiliation: Department of Human Genetics, Sri Ramachandra University, Porur, Chennai, Tamilnadu, India.
authors.forename: Sofi Beaula
authors.initials: SB
authors.lastname: Winfred
authors.affiliation: Department of Human Genetics, Sri Ramachandra University, Porur, Chennai, Tamilnadu, India.
authors.forename: Bhavani
authors.initials: B
authors.lastname: Mannivanan
authors.affiliation: Department of Human Genetics, Sri Ramachandra University, Porur, Chennai, Tamilnadu, India.
authors.forename: Hemadev
authors.initials: H
authors.lastname: Bhoopalan
authors.affiliation: Department of Bioinformatics, Alagappa University, Karaikudi, Tamilnadu, India.
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Shankar
authors.affiliation: Center for Toxicology and Developmental Research, Sri Ramachandra University, Porur, Chennai, Tamilnadu, India.
authors.forename: Sathiya
authors.initials: S
authors.lastname: Sekar
authors.affiliation: Department of Human Genetics, Sri Ramachandra University, Porur, Chennai, Tamilnadu, India.
authors.forename: Deepa Parvathi
authors.initials: DP
authors.lastname: Venkatachalam
authors.affiliation: Department of Community Medicine, Sri Ramachandra University, Porur, Chennai Tamilnadu, India.
authors.forename: Ravishankar
authors.initials: R
authors.lastname: Pitani
authors.affiliation: Department of Conservative Dentistry and Endodontics, Sri Ramachandra University, Porur, Chennai, Tamilnadu, India.
authors.forename: Venkateshbabu
authors.initials: V
authors.lastname: Nagendrababu
authors.affiliation: Central Research Facility, Sri Ramachandra University, Porur, Chennai, Tamilnadu, India.
authors.forename: Malini
authors.initials: M
authors.lastname: Thaiman
authors.affiliation: Department of Conservative Dentistry and Endodontics, Sri Ramachandra University, Porur, Chennai, Tamilnadu, India.
authors.forename: Kandaswamy
authors.initials: K
authors.lastname: Devivanayagam
authors.affiliation: Department of Bioinformatics, Alagappa University, Karaikudi, Tamilnadu, India.
authors.forename: Jeyakanthan
authors.initials: J
authors.lastname: Jayaraman
authors.affiliation: Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai, Tamilnadu, India.
authors.forename: Raghunathan
authors.initials: R
authors.lastname: Ragavachary
authors.affiliation: Department of Human Genetics, Sri Ramachandra University, Porur, Chennai, Tamilnadu, India.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Venkatraman
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001641:Bicuspid / Q000382:microbiology; D018441:Biofilms; D003198:Computer Simulation; D004331:Drosophila melanogaster; D004353:Drug Evaluation, Preclinical; D013293:Enterococcus faecalis / Q000187:drug effects; D005260:Female; D006801:Humans; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D046915:Penicillin-Binding Proteins / Q000737:chemistry; D011485:Protein Binding; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012388:Root Canal Irrigants / Q000737:chemistry / Q000494:pharmacology*; D012390:Root Canal Therapy; D012486:Salmonella typhimurium / Q000187:drug effects; D047090:beta-Lactams / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D046915:Penicillin-Binding Proteins; D011759:Pyrrolidines; D017382:Reactive Oxygen Species; D012388:Root Canal Irrigants; D047090:beta-Lactams