GroEL/ES inhibitors as potential antibiotics

Area of Science:

• Microbiology
• Drug Discovery
• Biochemistry

Background:

• The Escherichia coli GroEL/ES chaperonin system is essential for bacterial growth.
• Targeting essential bacterial systems with small molecules is a potential antibacterial strategy.
• Previous high-throughput screening identified 235 inhibitors of the E. coli GroEL/ES system.

Purpose of the Study:

• To evaluate the antibacterial activities of 22 GroEL/ES inhibitors against a panel of Gram-positive and Gram-negative bacteria.
• To identify selective inhibitors of the bacterial GroEL/ES system over human HSP60/10.
• To assess the cytotoxicity and identify lead candidates for further development.

Main Methods:

• Antibacterial activity screening of 22 GroEL/ES inhibitors against E. coli, B. subtilis, E. faecium, S. aureus, K. pneumoniae, A. baumannii, P. aeruginosa, and E. cloacae.
• Assessment of inhibition of the human HSP60/10 refolding cycle.
• Cytotoxicity evaluation against human liver and kidney cell lines.
• Determination of selectivity and potency of lead compounds.

Main Results:

• GroEL/ES inhibitors were more effective against Gram-positive bacteria, especially S. aureus, with low-μM to mid-nM activity.
• Some compounds selectively inhibited bacterial GroEL/ES over human HSP60/10.
• Compounds 8 and 18 showed >50-fold selectivity for S. aureus growth inhibition over cytotoxicity.
• Compounds 8 and 18 demonstrated potency comparable to existing antibiotics against sensitive and resistant S. aureus strains.

Conclusions:

• Small molecule inhibitors of the bacterial GroEL/ES chaperonin system exhibit significant antibacterial potential.
• Compounds 8 and 18 are promising lead candidates for developing novel antibiotics targeting S. aureus.
• The GroEL/ES chaperonin system represents a viable target for novel antibacterial drug discovery.