Bacterial cell killing by topoisomerase I mediated DNA lesion Grant

abstract

  • This project targets bacterial type IA topoisomerase for discovery of novel antibacterial drugs as countermeasure for multi-drug resistant bacterial pathogens, including gram negatives. Drugs that initiate cell killing by trapping the covalent cleavage complex formed by type IB and type IIA topoisomerases are widely used in current anti-cancer and anti-bacterial therapy. Accumulation of type IA topoisomerase cleavage complex can trigger rapid bacterial cell death via the oxidative cell death pathway but specific inhibitors of type IA bacterial topoisomerase I that can be developed into new antibacterial drugs remain to be discovered. The proposed research activities for the next funding period would develop and utilize rapid cell based applicable for HTS assay format to identify small molecule compounds that have antibacterial activity due to specific interaction with bacterial topoisomerase I. Inhibitors of bacterial topoisomerase I identified from screening would be analyzed biochemically for mechanism of action and structure activity relationship. Priority would be given to compounds with low toxicity that are active against gram negative Escherichia coli and Yersinia pestis in order to identify leads that can be used in development of therapeutic agents against gram negative pathogens. Bacterial proteins that process trapped topoisomerase cleavage complexes will be identified with genetic and biochemical experiments. The repair proteins involved may be useful new targets for combination therapy with antibiotics targeting both type IA and type IIA topoisomerases. Success in these proposed experiments would provide tools and leads for development of novel antibacterial drugs for the urgent public health problem of bacterial pathogens resistant to all current antibiotics.

date/time interval

  • September 1, 2012 - August 31, 2016

sponsor award ID

  • 7R01AI069313-07

local award ID

  • AWD000000002619

contributor

keywords

  • Adverse effects
  • Affinity
  • Anti-Bacterial Agents
  • Antibiotics
  • Bacteria
  • Bacterial DNA Topoisomerase I
  • Bacterial Proteins
  • Bacterial Typing
  • Binding
  • Biochemical
  • Biochemical Genetics
  • Biological Assay
  • Candidate Disease Gene
  • Cell Death
  • Cells
  • Cleaved cell
  • Code
  • Combined Modality Therapy
  • Complex
  • Computer Simulation
  • Cultured Cells
  • DNA
  • DNA Binding
  • DNA Topoisomerase IV
  • DNA Topoisomerases
  • DNA lesion
  • Detection
  • Development
  • Docking
  • Drug resistance
  • Enzymes
  • Escherichia coli
  • Excision
  • Family
  • Funding
  • Gel
  • Genes
  • Genetic
  • Growth
  • Human
  • Inhibitory Concentration 50
  • Lead
  • Lesion
  • Malignant Neoplasms
  • Measures
  • Mediating
  • Multi-Drug Resistance
  • Mutation
  • Pathway interactions
  • Pharmaceutical Preparations
  • Phosphotyrosine
  • Poisons
  • Process
  • Proteins
  • Public Health
  • Quinolones
  • Recombinants
  • Relaxation
  • Research Activity
  • Resistance
  • Saccharomyces cerevisiae
  • Screening procedure
  • Site
  • Speed
  • Structure
  • Structure-Activity Relationship
  • Temperature
  • Therapeutic
  • Therapeutic Agents
  • Topoisomerase
  • Topoisomerase-I Inhibitor
  • Toxic effect
  • Type I DNA Topoisomerases
  • Work
  • Yeasts
  • Yersinia pestis
  • analog
  • base
  • cancer therapy
  • cell killing
  • combat
  • counterscreen
  • design
  • endonuclease
  • global health
  • homologous recombination
  • improved
  • in vitro Assay
  • inhibitor/antagonist
  • mutant
  • novel
  • overexpression
  • pathogen
  • pharmacophore
  • phosphoric diester hydrolase
  • prevent
  • recombinational repair
  • repaired
  • research study
  • small molecule
  • small molecule libraries
  • success
  • tool