Microbial resistance: novel screens for a contemporary problem

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.