Related Experiment Videos
Microbial resistance: novel screens for a contemporary problem.
P B Fernandes1, R Menzel, D J Hardy
1Small Molecule Therapeutics, Inc., 11 Deer Park Drive, Suite 116, Monmouth Junction, New Jersey 08852, USA. fernandes@smtherapeutics.com
Medicinal Research Reviews
|November 11, 1999
Summary
New phenotype-based screens identify novel antibacterial agents targeting bacterial topoisomerase enzymes. These screens offer a promising approach to discovering new drugs to combat bacterial infections.
Area of Science:
- Microbiology
- Drug Discovery
- Biochemistry
Background:
- Natural products have historically yielded antibacterial agents, but discovery slowed significantly.
- Advances in biotechnology enabled cell-free screening and combinatorial synthesis for new drug discovery.
- Despite efforts, the discovery of new antibacterial agents has been limited in recent years.
Purpose of the Study:
- To develop novel phenotype-based screening methods for identifying antibacterial agents.
- To identify compounds targeting bacterial DNA gyrase, topoisomerase IV, and topoisomerase I.
- To characterize compounds that inhibit essential bacterial enzymes and exhibit antibacterial activity.
Main Methods:
- Development of phenotype-based screens leveraging natural enzyme physiology and biochemistry.
- Screening for bacterial DNA gyrase and topoisomerase IV poisons.
- Screening for compounds that induce DNA damage via interaction with bacterial topoisomerase I.
Main Results:
- A screen for bacterial DNA gyrase and topoisomerase IV poisons identified initial "hits" for further characterization.
- A second screen identified compounds interacting with bacterial topoisomerase I, causing DNA damage.
- Three identified compounds inhibited bacterial topoisomerase I, induced DNA cleavage, were noncytotoxic, and showed a Minimum Inhibitory Concentration (MIC) of 4.0 µg/mL against Staphylococcus aureus.
Conclusions:
- Phenotype-based screening offers a viable strategy for discovering novel antibacterial agents.
- Targeting bacterial topoisomerases is a promising avenue for developing new antibiotics.
- Identified compounds demonstrate potential as leads for new antibacterial therapies.